Benzimidazolinones, benzoxazolinones, benzopiperazinones, indanones, and derivatives thereof as inhibitors of factor Xa

ABSTRACT

The present application describes inhibitors of factor Xa of formula I:or pharmaceutically acceptable salt forms thereof, wherein W, W1, W2, and W3 may be N or C and J, Ja, and Jb combine to form a substituted carbocycle or heterocycle.

This application claims the benefit of U.S. Provisional Application Ser.No. 60/058,288, filed Sep. 9, 1997.

FIELD OF THE INVENTION

This invention relates generally to novel benzimidazolinones,benzoxazolinones, benzopiperazinones, indanones, and derivatives thereofas inhibitors of factor Xa, pharmaceutical compositions containing thesame, and methods of using the same as anticoagulant agents fortreatment and prevention of thromboembolic disorders.

BACKGROUND OF THE INVENTION

Activated factor Xa, whose major practical role is the generation ofthrombin by the limited proteolysis of prothrombin, holds a centralposition that links the intrinsic and extrinsic activation mechanisms inthe final common pathway of blood coagulation. The generation ofthrombin, the final serine protease in the pathway to generate a fibrinclot, from its precursor is amplified by formation of prothrombinasecomplex (factor Xa, factor V, Ca²⁺ and phospholipid). Since it iscalculated that one molecule of factor Xa can generate 138 molecules ofthrombin (Elodi, S., Varadi, K.: Optimization of conditions for thecatalytic effect of the factor IXa-factor VIII Complex: Probable role ofthe complex in the amplification of blood coagulation. Thromb. Res.1979, 15, 617-629), inhibition of factor Xa may be more efficient thaninactivation of thrombin in interrupting the blood coagulation system.

Therefore, efficacious and specific inhibitors of factor Xa are neededas potentially valuable therapeutic agents for the treatment ofthromboembolic disorders. It is thus desirable to discover new factor Xainhibitors.

EP 0,540,051 and JP 06227971 describe a series of compounds useful asfactor Xa inhibitors or to treat influenza based on the formula:

wherein A is an alkylene linker optionally substituted X is a bond, O,S, or carbonyl, n is 0-4, and Y is an optionally substituted carbocycleor heterocycle. The core ring containing Z can be a variety ofbenzofused heterocycles. However, the present invention does not involvecompounds containing these benzofused heterocycles-

Baker et al, in U.S. Pat. No. 5,317,103, discuss 5-HT₁ agonists whichare indole substituted five-membered heteroaromatic compounds of theformula:

wherein R¹ may be pyrrolidine or piperidine and A may be a basic groupincluding amino and amidino. Baker et al, however, do not appear todescribe heterocycles which are part of the present invention.

Baker et al, in WO 94/02477, discuss 5-HT₁ agonists which areimidazoles, triazoles, or tetrazoles of the formula:

wherein R¹ represents a nitrogen containing ring system or a nitrogensubstituted cyclobutane, and A may be a basic group including amino andamidino. But, the presently claimed invention doesn't relate to theheterocyclic cores of Baker et al.

EP 787,727 illustrates benzyl-thiazolidin-2,4-diones of the formula:

which are useful as hypoglycemic agents. However, these type ofcompounds are outside of the present Xa inhibitors.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novelinhibitors of factor Xa or pharmaceutically acceptable salts or prodrugsthereof.

It is another object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

It is another object of the present invention to provide a method fortreating thromboembolic disorders comprising administering to a host inneed of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or a pharmaceuticallyacceptable salt or prodrug form thereof.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors, discoverythat compounds of formula (I):

or pharmaceutically acceptable salt forms thereof, wherein W, W¹, W²,W³, J, J^(a), and J^(b) are defined below, are effective factor Xainhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in a first embodiment, the present invention provides a novelcompound of formula I:

or stereoisomer or pharmaceutically acceptable salt thereof, wherein;

one of W, W¹, W², and W³ is C—D and the remaining are C—R¹;

alternatively, W-W¹, W¹-W², or W²-W³ combine to form C(D^(a))N and theremaining are C—R¹;

D is selected from CN, C(═NR⁷)NR⁸R⁹, NHC(═NR⁷)NR⁸R⁹, NR⁸CH(═NR⁷),C(O)NR⁸R⁹, and (CH₂)_(t)NR⁸R⁹;

D^(a) is NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, or C₁₋₃ alkoxy;

J is selected from N(Z—A—B) and CR(Z—A—B); and

J^(a) and J^(b) together are selected from CONHCR^(e)R^(f),SO₂NHCR^(e)R^(f), (CR^(a)R^(b))_(q)SO₂NR^(d), and(CR^(a)R^(b))_(b)COCO(CR^(e)R^(f))_(c), wherein b+c=0 or 1;

alternatively, J and J^(a) together are selected from CON(Z—A—B)(CR^(c)R^(b))_(q) and N(Z—A—B)Q(R^(c)R^(b))_(a); and

J^(b) is selected from NR^(d), O, and CR^(e)R^(f);

Q is CO or CS;

alternatively, J, J^(a) and J^(b) together are selected from CR(Z—A—B)(CR^(a)R^(b))_(a)QNR^(d), CR(Z—A—B) (CR^(a)R^(b))_(d)C(O)O, CR(Z—A—B)NHCOCR^(e)R^(f), CR(Z—A—B)NHSO₂CR^(e)R^(f),N(Z—A—B)(CR^(a)R^(b))_(a)QNR^(d), N(Z—A—B)(CR^(a)R^(b)) C(O)O, N(Z—A—B)SO₂(CR^(c)R^(b))_(a)CR^(e)R^(f), N(Z—A—B) SO₂(CR^(c)R^(b))_(a)NR^(d),CON(Z—A—B)CR^(e)R^(f), CONR^(b)(CR^(c)R^(b))_(a)N(Z—A—B),

R is selected from H, C₁₋₆ alkyl, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂,OH, C₁₋₆ alkoxy, C₁₋₆ alkoxy-C₁₋₄ alkyl, (CH₂)_(t)NR⁸R⁹, 5-6 memberedaromatic heterocyclyl-C₁₋₄ alkyl, and aryl-C₁₋₄ alkyl, wherein thearomatic heterocyclyl and aryl groups are substituted with 0-1 R⁴;

R^(a) is selected from H, C₁₋₆ alkyl, C(O)R^(2b), 5-6 membered aromaticheterocyclyl-C₁₋₄ alkyl, and aryl-C₁₋₄ alkyl, wherein the aromatichetercyclyl and aryl groups are substituted with 0-1 R⁴;

R^(b) is H or C₁₋₂ alkyl;

R^(c) is selected from H, C₁₋₆ alkyl, C(O)R^(2b), S(O)_(p)R^(2b), BO₂H₂,5-6 membered aromatic heterocyclyl-C₁₋₄ alkyl, and aryl-C₁₋₄ alkyl,wherein the aromatic hetercyclyl and aryl groups are substituted with0-1 R⁴;

R^(d) is selected from H, OH, NH₂, C₁₋₂ alkyl, and C₁₋₂ alkyl-OH,

alternatively, R^(c) and R^(d), when attached to adjacent atoms,together form a double bond;

R^(e) is selected from H, OH, NH₂, C₁₋₂ alkyl, and C₁₋₂ alkyl-OH,

alternatively, R^(c) and R^(e), when attached to adjacent atoms,together form a double bond;

R^(f) is H or C₁₋₂ alkyl;

Z is selected from a bond, C₁₋₄ alkylene, (CH₂)_(r)O(CH₂)_(r),(CH₂)_(r)NR³(CH₂)_(r), (CH₂)_(r)C(O)(CH₂)_(r), (CH₂)_(r)C(O)(CH₂)_(r),(CH₂)_(r)OC(O)(CH₂)_(r), (CH₂)_(r)C(O)NR³(CH₂)_(r),(CH₂)_(r)NR³C(O)(CH₂)_(r), (CH₂)_(r)OC(O)O(CH₂)_(r), (CH₂)_(r)OC(O)NR³(CH₂)_(r), (CH₂)_(r)NR³C(O) O(CH₂)_(r), (CH₂)_(r)NR³C(O)NR³(CH₂)_(r),(CH₂)_(r)S(O)_(p)(CH₂)_(r), (CH₂)_(r)SO₂NR³(CH₂)_(r), (CH₂)_(r)NR³SO₂(CH₂)_(r), and (CH₂)_(r)NR³SO₂NR³(CH₂)_(r), provided that Z does notform a N—N, N—O, N—S, NCH₂N, NCH₂O, or NCH₂S bond with the groups towhich it is attached;

R¹, at each occurrence, is selected from H, F, Cl, Br, I, (CF₂)_(r)CF₃,OR², NR²R^(2a), C(O)R^(2b), (CF₂)_(r)CO₂R², S(O)₂R^(2b), NR²C(O)R^(2b),C(O)NR²R^(2a), SO₂NR²R^(2a), C₃₋₆ carbocyclic residue substituted with0-2 R⁴, and 5-10 membered heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O, and S andsubstituted with 0-2 R⁴;

R¹′, at each occurrence, is selected from H, C₁₋₃ alkyl, F, Cl, Br, I,—CN, —CHO, (CF₂)_(r)CF₃, (CH₂)_(r)OR²C NR²R^(2a), C(O)R^(2c), OC(O)R²,(CF₂)_(r)CO₂R²C, S(O)_(p)R^(2b), NR²(CH₂)_(r)OR², CH(═NR²C)NR²R^(2a),NR²C(O)R^(2b), NR²C(O)NHR^(2b), NR²C(O)₂R^(2a), OC(O)NR^(2a)R^(2b),C(O)NR²R^(2a), C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a), —NR²SO₂R^(2b), C₃₋₆carbocyclic residue substituted with 0-2 R^(4b), and 5-10 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S substituted with 0-2 R^(4b);

R¹″, at each occurrence, is selected from H, CH(CH₂OR²)2, C(O)R^(2c),C(O)NR²R^(2a), S(O)R^(2b), S(O)₂R^(2b), and SO₂NR²R^(2a); R², at eachoccurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆carbocyclic residue substituted with 0-2 R^(4b), and 5-6 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S and substituted with 0-2 R^(4b);

R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl,C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S and substituted with 0-2 R^(4b);

alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a 5 or 6 membered saturated, partiallysaturated or unsaturated ring substituted with 0-2 R^(4b)and containingfrom 0-1 additional heteroatoms selected from the group consisting of N,O, and S;

R^(2b)is selected from CF₃, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆carbocyclic residue substituted with 0-2 R^(4b), and 5-6 memberedheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S and substituted with 0-2 R^(4b);

R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and5-6 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R^(4b);

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

A is selected from:

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁴, and

5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S and substituted with0-2 R⁴;

B is selected from: H, Y, and X—Y;

X is selected from C₁₋₄ alkylene, —CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—,—C(═NR¹″)—, —CR²(NR¹″R²)—, —CR²(OR²)—, —CR²(SR²)—, —C(O)CR²R^(2a)—,—CR²R^(2a)C(O), —S(O)_(p)—, —S(O)_(p)CR²R^(2a)—, —CR²R^(2a)S(O)_(p)—,—S(O)2NR²—, —NR²S(O)2—, —NR²S(C)₂CR²R^(2a)—, —CR²R^(2a)S(O)₂NR²—,—NR²S(O)2NR²—, —C(O)NR²—, —NR²C(O)—, —C(O)NR²CR²R^(2a)—,—NR²C(O)CR²R^(2a)—, CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—, —NR²C(O)O—,—OC(O)NR²—, —NR²C(O)NR²—, —NR²—, —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O,—CR²R^(2a)O—, and —OCR²R^(2a)—;

Y is selected from:

(CH₂)_(r)NR²R^(2a), provided that X—Y do not form a N—N, O—N, or S—Nbond,

C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and

5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R^(4a);

R⁴, at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², F, Cl, Br,I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R²C,NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a), CH(═NR²)NR²R^(2a),CH(═NS(O)₂R⁵)NR²R^(2a), NHC(═NR²)NR²R^(2a), C(O)NHC(═NR²)NR²R^(2a),SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵,(CF₂)_(r)CF₃, NCH₂R¹″, OCH₂R¹″, SCH₂R¹″, N(CH₂)₂(CH₂)_(t)R¹′,O(CH₂)₂(CH₂)_(t)R¹′, and S(CH₂)₂(CH₂)_(t)R¹′;

alternatively, one R⁴ is a 5-6 membered aromatic heterocycle containingfrom 1-4 heteroatoms selected from the group consisting of N, O, and S;

R^(4a), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR²,(CH₂)_(r)—F, (CH₂)_(r)—Br, (CH₂)_(r)—Cl, I, C₁₋₄ alkyl, —CN, NO₂,(CH₂)_(r)NR²R^(2a), (CH₂)_(r)NR²R^(2b), (CH₂)_(r)C(O)R²C, NR²C(O)R^(2b),C(O)NR²R^(2a), C(O)NH(CH₂)₂NR²R^(2a), NR²C(O)NR²R^(2a),CH(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a),NR²SO₂—C₁₋₄ alkyl, C(O)NHSO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and(CF₂)_(r)CF_(3;)

alternatively, one R^(4a) is a 5-6 membered aromatic heterocyclecontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S;

R^(4b), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR³, F, Cl,Br, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³,(CH₂)_(r)C(O)OR³C, NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O)NR³R^(3a),CH(═NR³)NR³R^(3a), NH³C(═NR³)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a),NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄alkyl, S(O)_(p)-phenyl, and (CF₂)_(r)CF_(3;)

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenylsubstituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶;

R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r)OR², F, Cl, Br,I, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b),NR²C(O)R^(2b), NR²C(O)NR²R^(2a), CH(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a),NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₄ alkyl;

R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, C₆₋₁₀ aryloxy, C₆₋₁₀aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄alkoxycarbonyl, C₆₋₁0 arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl;

R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and (CH₂)_(n)-phenyl;

R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and (CH₂)_(n)-phenyl;

a, at each occurrence, is selected from 0, 1, and 2;

d, at each occurrence, is selected from 0 and 1;

n, at each occurrence, is selected from 0, 1, 2, and 3;

m, at each occurrence, is selected from 0, 1, and 2;

p, at each occurrence, is selected from 0, 1, and 2;

q, at each occurrence, is selected from 1 and 2;

r, at each occurrence, is selected from 0, 1, and 2;

s, at each occurrence, is selected from 0, 1, and 2; and,

t, at each occurrence, is selected from 0 and 1;

provided that A—B is other than benzyl-thiazolidin-2,4-dione.

[2] In a preferred embodiment, the present invention provides a novelcompound of formula I, wherein;

one of W, W¹, W², and W³ is C—D and the remaining are C—R¹;

J is selected from N(Z—A—B) and CR(Z—A—B); and

J^(a) and J^(b) together are selected from CONHCR^(e)R^(f),SO₂NHCR^(e)R^(f), (CR^(a)R^(b))_(q)SO₂NR^(d), and(CR^(a)R^(b))_(b)COCO(CR^(e)R^(f))_(c), wherein b+c=0 or 1;

alternatively, J and J^(a) together are selected fromCON(Z—A—B)(CR^(c)R^(b)) and N(Z—A—B)Q(R^(c)R^(b))_(a); and

J^(b) is selected from NR^(d), O, and CR^(e)R^(f);

Q is CO;

alternatively, J, J^(a) and J^(b) together are selected fromCR(Z—A—B)(CR^(a)R^(b))_(a)QNR^(d), CR(Z—A—B)(CR^(a)R^(b))_(d)C(O)O,CR(Z—A—B) NHCOCR^(e)R^(f), CR(Z—A—B) NHSO₂CR^(e)R^(f),N(Z—A—B)(CR^(a)R^(b))_(a)QNR^(d), N(Z—A—B)(CR^(a)R^(b))C(O)O,N(Z—A—B)SO₂(CR^(c)R^(b))_(a)CR^(e)R^(f),N(Z—A—B)SO₂(CR^(c)R^(b))_(a)NR^(d), CON(Z—A—B)CR^(e)R^(f), andCONR^(b)(CR^(c)R^(b))_(a)N(Z—A—B)

Z is selected from a CH₂O, OCH₂, CH₂NH, NHCH₂, CH₂C(O), C(O)CH₂, C(O)NH,C(O)NH, CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and SO₂NH;

B is selected from: Y, X—Y, and NR²R^(2a);

Y is selected from one of the following carbocyclic and heterocyclicsystems which are substituted with 0-2 R^(4a);

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl,morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole,triazole, 1,2,3-oxadiazole, 1,2,4- oxadiazole, 1,2,5-oxadiazole,1,3,4-oxadiazole, 1,2,3- thiadiazole, 1,2,4-thiadiazole,1,2,5-thiadiazole, 1,3,4- thiadiazole, 1,2,3-triazole, 1,2,4-triazole,1,2,5- triazole, 1,3,4-triazole, benzofuran, benzothiofuran, indole,benzimidazole, benzoxazole, benzthiazole, indazole, benzisoxazole,benzisothiazole, and isoindazole;

Y may also be selected from the following bicyclic heteroaryl ringsystems:

K is selected from O, S, NH, and N; and,

a, at each occurrence, is selected from 0 and 1.

[3] In an even more preferred embodiment, the present invention providesa novel compound of formula Ia,

or stereoisomer or pharmaceutically acceptable salt thereof, wherein;

D is C(═NR⁷) NR⁸R⁹;

J is selected from N(Z—A—B) and CR(Z—A—B); and

J^(a) and J^(b) together are selected from CONHCR^(e)R^(f);

alternatively, J and J^(a) together are selected fromCON(Z—A—B)(CR^(c)R^(b)) and N(Z—A—B)Q(R^(c)R^(b))_(a); and

J^(b) is selected from NR^(d), O, and CR^(e)R^(f);

Q is CO;

alternatively, J, J^(a) and J^(b) together are selected fromCR(Z—A—B)(CR^(a)R^(b))_(a)QNR^(d), CR(Z—A—B)(CR^(a)R^(b))_(d)C(O)O,N(Z—A—B)(CR^(a)R^(b))_(a)QNR^(d), N(Z—A—B)(CR^(a)R^(b))C(O)O,CON(Z—A—B)CR^(e)R^(f), and CONR^(b)(CR^(c)R^(b))_(a)N(Z—A—B);

A is selected from:

piperidinyl,

piperazinyl, C₅₋₆ carbocyclic residue substituted with 0-2 R⁴, and

5-6 membered heteroaryl containing from 1-4 heteroatoms

selected from the group consisting of N, O, and S and substituted with0-2 R⁴; and,

B is selected from: Y and X—Y.

[4] In an even more preferred embodiment, the present invention providesa novel compound of formula Ia, wherein

J and J^(a) together are N(Z—A—B)C(O); and

J^(b) is selected from NR^(d), O, and CR^(e)R^(f);

alternatively, J, J^(a) and J^(b) together are CR(Z—A—B)C(O)NR^(d);

Y is selected from one of the following carbocyclic and heterocyclicsystems which are substituted with 0-2 R⁴a;

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl,morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, benzimidazole,oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole,1,2,4-triazole, 1,2,5- triazole, and 1,3,4-triazole.

[5] In a still further preferred embodiment, the present inventionprovides a novel compound selected from:

1N-(2′-Aminosulfonyl-[1,1′]biphenylamino)carbonylmethyl-6-amidinobenzimidazolinone;

1N-(2′-Aminosulfonyl-[1,1′]biphenylamino)-carbonylmethyl-5-amidinobenzimidazolinone;

1N-[4′-(p-chlorophenyl)thiazolyl-2′-amino)carbonylmethyl-6-amidinobenzimidazolinone;

5-Amidino-1N-(1′N-(4′-benzylpiperidino)carbonylmethyl)benzimidazolinone;

1N-(2′-Aminosulfonyl-[1,1′]biphenylamino)carbonylmethyl-3N-0-hydroxyethylene-6-amidinobenzimidazolinone;

1N-(1′N-(2′-aminosulfonyl-[1,1′]-biphenylamino)carbonylmethyl)-6-amidinobenzoxazolinone;

1N-(N-p-(41-oxazolyl)phenylamino)carbonylmethyl-6-amidino-benzoxazolinone;

1N-(1′N-(4′N-benzylsulfonylpiperazino)carbonylmethyl-6-amidino-benzoxazolinone;

7-amidino-1N-(4′-bromophenyl)carbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one;

7-amidino-1N-(3′-amino-[1,1′]biphenyl)carbonyl-methyl-3,4-dihydroquinoxalin-2(1H)-one;

7-amidino-1N-(43-fluoro-[1,1′]biphenyl)carbonyl-methyl-3,4-dihydroquinoxalin-2(1H)-one;

7-amidino-1N-[1,1′]-biphenylcarbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one;

7-amidino-1N-(2′-tert-butylsulfonamido-[1,1′]biphenyl)carbonylmethyl-3,4-dihydroquinoxalin- 2(1H)-one;

7-amidino-1N-(2′-sulfonamido-[1,1′]-biphenyl)-carbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one;

1N-(2′-aminosulfonyl-[1,1′]biphenylamino)carbonyl-methyl-7-amidino-3,4-dihydroquinoxalin-2(1H)-one;

6-amidino-1N-[1,1′]-biphenyl)carbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one;

1N-[1,1′]Biphenylcarbonyl)ethyl-6-amidinobenzoxazolinone;

1-([1,1′]-Biphenylcarbonyl)ethyl-6-amidino-3N- methylbenzimidazolinone;

1-([1,1′]-biphenylcarbonyl)ethyl-6-amidinobenzimidazolinone;

1N-(4-Bromophenylcarbonyl)ethyl-6-amidinobenzoxazolinone;1N-[4-(2-Aminosulfonylphenyl)pyridin-2-yl]aminocarbonylmethyl-6-amidinobenzoxazolinone;

1N-(4-Morpholinosulfonamidophenyl)aminocarbonylmethyl-6-amidinobenzoxazolinone;

3-(3-methoxy-(2′-aminosulfonyl-[1,1′]biphenyl-1-aminocarbonyl)methyl-5-amidino-2-indolinone;

3-(3-amino-(2′-aminosulfonyl-[1,1′]--biphenylaminocarbonyl)methyl-5-amidino-2-indolinone;

3-(3-hydroxy-(2′-aminosulfonyl-[1,1′]-biphenylaminocarbonyl)methyl-5-amidino-2-indolinone;

3-(3′-hydroxy-(2-chloro-(21-aminosulfonyl)-[1,1′]-biphenylaminocarbonyl)methyl-5-amidino-2-indolinone;

3-(3′-amino-(2-chloro-(2′-aminosulfonyl)-[1,1′]-biphenylaminocarbonyl)methyl-5-amidino-2-indolinone;

3-(2-chloro-(2′-aminosulfonyl)-[1,1′]biphenyl-31-aminocarbonyl)methyl-5-amidino-2-indolinone;

3-(2-bromo-(2′-aminosulfonyl)-[1,1′]biphenyl-31-aminocarbonyl)methyl-5-amidino-2-indolinone;

3-(2-fluoro-(2′-aminosulfonyl)-[1,1′]biphenyl-3′-aminocarbonyl)methyl-5-amidino-2-indolinone; and,

3-(2′-aminosulfonyl)-[1,1′]biphenyl-3′-aminocarbonyl)methyl-5-amidino-2-indolinone.

[6] In another preferred embodiment, the present invention provides acompound of the formulae a-c:

or stereoisomer or pharmaceutically acceptable salt form thereof.

In a preferred embodiment, the present invention provides a compound ofthe formula:

In a third embodiment, the present invention provides novelpharmaceutical compositions, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt form thereof.

In a fourth embodiment, the present invention provides a novel methodfor treating or preventing a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt form thereof.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

When any variable (e.g., R⁶) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R⁶, then saidgroup may optionally be substituted with up to two R⁶ groups and R⁶ ateach occurrence is selected independently from the definition of R⁶.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “C₁₋₆ alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, examples of which include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl; “Alkenyl” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more unsaturated carbon-carbon bonds which may occur in anystable point along the chain, such as ethenyl, propenyl, and the like.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, sulfate, and thelike.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3- to 7-membered monocyclic or bicyclic or 7- to13-membered bicyclic or tricyclic, any of which may be saturated,partially unsaturated, or aromatic. Examples of such carbocyclesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” isintended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which is saturated partiallyunsaturated or unsaturated (aromatic), and which consists of carbonatoms and from 1 to 4 heteroatoms independently selected from the groupconsisting of N, O and S and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Thenitrogen and sulfur heteroatoms may optionally be oxidized. Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom which results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. If specifically noted, anitrogen in the heterocycle may optionally be quaternized. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1. As used herein, the term “aromatic heterocyclic system”is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or7- to 10-membered bicyclic heterocyclic aromatic ring which consists ofcarbon atoms and from 1 to 4 heterotams independently selected from thegroup consisting of N, O and S. It is preferred that the total number ofS and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H- pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H- quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H- 1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H- indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoguinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5- thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are notlimited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl,benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl.Also included are fused ring and spiro compounds containing, forexample, the above heterocycles.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

“Prodrugs” are intended to include any covalently bonded carriers whichrelease the active parent drug according to formula (I) in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of acompound of formula (I) are prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs include compounds of formula (I) wherein a hydroxy,amino, or sulfhydryl group is bonded to any group that, when the prodrugor compound of formula (I) is administered to a mammalian subject,cleaves to form a free hydroxyl, free amino, or free sulfhydryl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds of formula (I), and the like.Preferred prodrugs are amine prodrugs the amine group is attached to agroup selected from OH, C₁₋₄ alkoxy, C₆₋₁₀ aryloxy, C₁₋₄ alkoxycarbonyl,C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxyC₁₋₄ alkoxycarbonyl, and C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl. Morepreferred prodrugs are OH, methoxy, ethoxy, benzyloxycarbonyl,methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

SYNTHESIS

The compounds of Formula I can be prepared using the reactions andtechniques described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. It will also berecognized that another major consideration in the planning of anysynthetic route in this field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. An authoritative accountdescribing the many alternatives to the trained practitioner is Greeneand Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).

The generic cores depicted in Scheme 1 can be made from nitro compoundsor from the replacement of the corresponding halogen with the HNR^(d)-or HO-fragments in the presence of a base. Reduction of the nitro groupcan provide anilines. Cyclization of the anilines with formic acid,trialkylorthoformate, phosgene, carbon disulfide, sulfuryl chloride,oxalyl chloride, α-chloroacetyl chloride, β- chloroacetyl chloride,α-chloroacetal, β-chloroacetate, α- chlorosulfonyl chloride, orβ-chlorosulfonyl chloride can form the cyclic cores. Alkylation of theNH on the new formed ring with halo-ZAB can provide the desiredcompound.

The thioamides and thioesters of the present invention can be obtainedfrom the corresponding amides and esters by treatment with P₂S₅ in thepresence of a base, or with Lawesson's reagent (T. Nishio et al,Synthesis 1989, 5, 396).

The 6,6-fused compounds described in Scheme 2 can be prepared startingwith nucleophilic substitution of the aryl fluoride with HJ^(a)J^(b)NHPin the presence of a base. fter removal of the protecting group P,intramolecular cyclization with a dehydration reagent can give thedesired cores. Alternatively, dehydration of the acid withHJ^(a)J^(b)NH₂, followed by intramolecular nucleophilic substitution ofthe aryl fluoride by the J^(b)H-fragment in the presence of a base, cangive the desired cores. Furthermore, Ω-(2-bromo- phenyl)alkylamines canreact with carbon monoxide in the presence of palladium catalyst to givethe desired cores.

The generic cores depicted in Scheme 3 can be prepared from N-protectedo-halo-anilines. The anilines can also be made from the non-protectedanilines or the nitro precursors. Palladium catalyzed coupling reactionof the halides with zinc reagents containing vinyl functionality cangive the coupled compounds. In the presence of palladium catalyst.intramolecular cyclizations can produce ring closed compounds, which canbe oxidized with MCPBA to give the 3-oxo cores. The 3-oxo derivativescan be further elaborated, followed by the N-alkylation with halo-ZAB,to provide the desired compounds.

The N-substituted cores illustrated in Scheme 4 can be obtained fromN-protected o-halogen anilines. Metal catalyzed coupling of the halidewith a zinc reagent which contains an ester functionality can give thecoupled compound. Deprotection of the P-group from the nitrogen can givethe cyclic compound. Further elaboration and N-alkylation can beperformed as described previously.

Bromine on commercially available 5-bromoisatin can be converted toother functionalities by palladium catalyzed cross coupling reactionsand nucleophilic replacements. The desired compounds can then beobtained by N-alkylation with halo-ZAB.

Scheme 6 provides a route to some of the diketones of the presentinvention. Oxidation of o-allylaniline (see Scheme 3) with MnO₂ canprovide a ketone. The ketone can then undergo Michael addition, followedby quenching with chiorosilane, to give the cyclic vinyl silylether. Thevinyl silylether can be oxidized with NMMO in the presence of OsO₄ toform the α- hydroxyketone, which can be further oxidized with Pb(OAc)4in pyridine to form the diketone. The desired compound can be obtainedby N-alkylation with an appropriate halo-ZAB.

Preparation of additional diketones is shown in Scheme 7. Nucleophilicsubstitution of the aryl fluoride with 2- ketosuccinic acid monomethylester, followed by decarboxylation, can give β-aryl-α-ketoester.Protection of the carbonyl group, reduction of the nitro group, anddeprotection of the carbonyl group can afford the final intermediatewhich is then cyclized and alkylated.

6,6-Fused ureas/sulfonylureas can be made as shown in Scheme 8 (J═CO,SO₂). Bromination of 2-methyl nitrobenzene with NBS can give the benzylbromide, which can be readily converted into the amine. After reductionof the nitro group, cyclization with COCl₂ or SO₂Cl₂ can afford thedesired cores.

Scheme 9 illustrates a route to fused sulfonamides. Addition of NaHSO₃to the olefin (see Scheme 3) can give the corresponding sulfuric acid(Li, C. Synthesis 1991, 244). Removal of the P-group and thendehydration with the sulfuric acid can provide sulfonamide, which canundergo N-alkylation to afford the desired products.

In Scheme 10 is shown a route to a 6,5-fused sulfonamide. N-alkylationof the aniline with halo-ZAB, followed by treatment with ClCH₂SO₂Cl anda base, can give the desired core (Wojciechowski, K. Synthesis 1992,571).

The 6,5-fused heterocyclic rings wherein J^(b) is N-R^(d) or O areprepared by rhodium coupling with an appropriate azide, Cl—Q—CH(R)N₂(Scheme 11). Deprotonation of the benzylic -methine with LDA at followedby addition of the corresponding halo-ZAB affords the desired product.

Synthesis of the 6,6-fused heterocycles (J^(b) is N-R^(d) or O) may beobtained via radical addition to an acetylene derivative as shown (e.g.,Bu₃SnH) or transmetallation of the aromatic bromine with n-BuLi orpalladium coupling with Pd(OAc)₂ and finally quenching with the desiredRa-halo compound to afford the intermediate shown in Scheme 12. Cuprateaddition (Li(CN)Cu—Z—A—B) and quenching again with the appropriateR^(b)-halo compound should afford the desired 6,6- fused heterocycletarget.

Acylation of an anilino or phenolic starting reagent (J^(b)═N—R^(d) orO) with a functionalized methyl ester acid chloride followed bysaponification should afford the desired acid intermediate (Scheme 13).Chlorination to the acid chloride with thionyl chloride can afford theacid chloride intermediate which can then subjected to the FriedelCrafts conditions to afford the target heterocycle. The resultingheterocycle may be further functionalized via a Wittig olifination,followed by hydrogenation and alkylation to yield the fullyfunctionalized heterocycle. The benzylic Z-group can then coupled to theA—B groups to afford the target compound.

The 6,6 sulfonamides in Scheme 14 may be prepared from the appropriatehalo sulfonamide using NaOH and DMSO (Synthesis 1992, (6), 571-6).Alkylation with NaH and halo- ZAB should afford the desired target. Thissame method may be used to prepared the 6,6-fused cyclic amides inScheme 15.

5,6-Fused isatins can be prepared from the corresponding indanone(Scheme 16). Oxidation with SeO₂ in acetic acid followed by alkylationor bromination/hydrolysis should afford the key isotin intermediate (J.Chem. Soc., Perkin Trans. 1995, 1(24), 3117-24). This may then alkylatedwith the corresponding halo-ZAB to afford the desired isatin target.

The 6,6-fused carbocycles shown in Scheme 17 may be prepared from thecorresponding 3-tetralone via alkylation with NaH R-halo or NBS,followed by a second alkylation with halo-ZAB. Oxidation with SeO₂affords the desired diketone which is then dialkylated with R^(e)-haloand R^(f)-halo sequentially using NaH as the base to yield the desiredtarget.

Preparation of group A—B of FORMULA I

Compounds of this invention where B is either a carbocyclic orheterocyclic residue as defined in Formula I are coupled to A as showngenerically and by specific example in Schemes 18 and 19, respectively.Either or both of A and B may be substituted with 0-2 R⁴. W is definedas a suitable protected nitrogen, such as NO₂ or NHBOC; a protectedsulfur, such as S—tBu or SMOM; or a methyl ester. Halogen-metal exchangeof the bromine in bromo-B with n-butyl lithium, quenching withtriisopropyl borate and acidic hydrolysis gives the required boronicacid, B—B(OH)₂X The W—A—Br subunit may be already linked to ring Mbefore the Suzuki coupling reaction. Deprotection provides the completesubunit.

Scheme 19 describes a typical example of how the A—B subunit is preparedfor attachment to ring M. 4-Bromoaniline is protected as Boc-derivativeand the coupled to 2-(t- butylamino)sulfonylphenylboronic acid underSuzuki conditions. 30 2-(t-Butylamino)sulfonylphenylboronic acid isprepared by the method described by Rivero (Bioorg. Med. Chem. Lett.1994, 189). Deprotection with TFA can provide the aminobiphenylcompound. The aminobiphenyl is then coupled to the core ring structuresas described below.

When B is defined as X—Y, the following description applies. Groups Aand B are available either through commercial sources, known in theliterature or readily synthesized by the adaptation of standardprocedures known to practitioners skilled in the art of organicsynthesis. the required reactive functional groups appended to analogsof A and B are also available either through commercial sources, knownin the literature or readily synthesized by the adaptation of standardprocedures known to practitioners skilled in the art of synthesis. Inthe tables that follow the chemistry required to effect the coupling ofA to B is outlined.

TABLE A Preparation of Amide Ester, Urea, Sulfonamide and SulfamideLinkages Between A and B. If A then the reactive to give the followingcontains substituent of Y is: product A—X—Y: A—NHR² as a ClC(O)—YA—NR²—C(O)—Y substituent a secondary NH ClC(O)—Y A—C(O)—Y NH as part ofa ring or chain A—OH as a ClC(O)—Y A—O—C(O)—Y substituent A—NHR² as aClC(O)—CR²R^(2a)—Y A—NR²—C(O)—CR²R^(2a)—Y substituent a secondaryClC(O)—CR²R^(2a)—Y A—C(O)—CR²R^(2a)—Y NH as part of a ring or chain A—OHas a ClC(O)—CR²R^(2a)—Y A—O—C(O)—CR²R^(2a)—Y substituent A—NHR² as aClC(O)—CNR²—Y A—NR²—C(O)—CNR²—Y substituent a secondary ClC(O)—CNR²—YA—C(O)—CNR²—Y NH as part of a ring or chain A—OH as a ClC(O)—CNR²—YA—O—C(O)—CNR²—Y substituent A—NHR² as a ClSO₂—Y A—NR²—SO₂—Y substituenta secondary ClSO₂—Y A—SO₂—Y NH as part of a ring or chain A—NHR² as aClSO₂—CR²R^(2a)—Y A—NR²—SO₂—CR²R^(2a)—Y substituent a secondaryClSO₂—CR²R^(2a)—Y A—SO₂—CR²R^(2a)—Y NH as part of a ring or chain A—NHR²as a ClSO₂—NR²—Y A—NR²—SO₂—NR²—Y substituent a secondary ClSO₂—NR²—YA—SO₂—NR²—Y NH as part of a ring or chain A—C(O)Cl HO—Y as a substituentA—C(O)—O—Y A—C(O)Cl NHR²—Y as a A—C(O)—NR²—Y substituent A—C(O)Cl asecondary NH as A—C(O)—Y part of a ring or chain A—CR²R^(2a)- HO—Y as asubstituent A—CR²R^(2a)C(O)—O—Y C(O)Cl A—CR²R^(2a)- NHR²—Y as aA—CR²R^(2a)C(O)—NR²—Y C(O)Cl substituent A—CR²R^(2a)- a secondary NH asALCR²R^(2a)C(O)—Y C(O)Cl part of a ring or chain A—SO₂Cl NHR²—Y as aA—SO₂—NR²—Y substituent A—SO₂Cl a secondary NH as A—SO₂—Y part of a ringor chain A—CR²R^(2a)- NHR²—Y as a A—CR²R^(2a)SO₂—NR²—Y SO₂Cl substituentA—CR²R^(2a)- a secondary NH as A—CR²R^(2a)SO₂—Y SO₂Cl part of a ring orchain

The chemistry of Table A can be carried out in aprotic solvents such asa chlorocarbon, pyridine, benzene or toluene, at temperatures rangingfrom −20° C. to the reflux point of the solvent and with or without atrialkylamine base.

TABLE B Preparation of Ketone Linkages between A and B. If A then thereactive to give the following contains: substituent of Y is: productA—X—Y: A—C(O)Cl BrMg—Y A—C(O)—Y A—CR²R^(2a)C(O)Cl BrMg—YA—CR²R^(2a)C(O)—Y A—C(O)Cl BrMbCR²R^(2a)—Y A—C(O)CR²R^(2a)—YA—CR²R^(2a)C(O)Cl BrMgCR²R^(2a)—Y A—CR²R^(2a)C(O)CR²R^(2a)—Y

The coupling chemistry of table B can be carried out by a variety ofmethods. The Grignard reagent required for Y is prepared from a halogenanalog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0° C. tothe reflux point of the solvent. This Grignard reagent can reacteddirectly under very controlled conditions, that is low temperature (−20°C. or lower) and with a large excess of acid chloride or with catalyticor stoichiometric copper bromideedimethyl sulfide complex in dimethylsulfide as a solvent or with a variant thereof. Other methods availableinclude transforming the Grignard reagent to the cadmium reagent andcoupling according to the procedure of Carson and Prout (Org. Syn. Col.Vol. 3 601, 1955) or coupling mediated by Fe(acac)₃ according toFiandanesse et al. (Tet. Lett., 4805, 1984), or a coupling mediated bymanganese(II) catalysis (Cahiez and Laboue, Tet. Lett., 33(31), 4437,1992).

TABLE C Preparation of Ether and Thioether linkages between A and B. IfA then the reactive to give the following contains: substituent of Y is:product A—X—Y: A—OH Br—Y A—O—Y A—CR²R^(2a)—OH Br—Y A—CR²R^(2a)O—Y A—OHBr—CR²R^(2a)—Y A—OCR²R^(2a)—Y A—SH Br—Y A—S—Y A—CR²R^(2a)—SH Br—YA—CR²R^(2a)S—Y A—SH Br—CR²R^(2a)—Y A—SCR²R^(2a)—Y

The ether and thioether linkages of Table C can be prepared by reactingthe two components in a polar aprotic solvent such as acetone,dimethylformamide or dimethylsulfoxide in the presence of a base such aspotassium carbonate, sodium hydride or potassium t-butoxide at atemperature ranging from ambient to the reflux point of the solventused.

TABLE D Preparation of —SO—and —SO₂—linkages from thioether of Table C.then it is oxidized then it is oxidized If the with wet with m— startingAlumina/Oxone to chloroperbenzoic acid material is: give: to give: A—S—YA—S(O)—Y A—SO₂—Y A—CR²R^(2a)S—Y A—CR²R^(2a)S(O)—Y A—CR²R^(2a)SO₂—YA—SCR²R^(2a)—Y A—S(O)CR²R^(2a)—Y A—SO₂CR²R^(2a)—Y

The thioethers of Table C serve as a convenient starting material forthe preparation of the sulfoxide and sulfone analogs of Table D. Acombination of wet alumina and Oxone can provide a reliable reagents forthe oxidation of the thioether to the sulfoxide as shown by Greenhalgh(Syn. Lett. 1992, 235). The sulfone can be prepared according to themethod of Satoh (Chem. Lett. 1992, 381) using m- chloroperbenzoic acid.

A compund of Formula I may have more than one isomer and one of theisomers may display superior activity compared with the other. Thus,each isomer is contemplated to be a part of the present invention. Forexample, both stereoisomers of the following indolinones are consideredto be part of the present invention.

When required, separation of the racemic material can be achieved byHPLC using a chiral column or by a resolution using a resolving agentsuch as camphonic chloride as in Steven D. Young, et al, AntimicrobialAgents and Chemotheraphy, 1995, 2602-2605. A chiral compound of FormulaI may also be directly synthesized using a chiral catalyst or a chiralligand, e.g. Andrew S. Thompson, et al, Tet. lett. 1995, 36, 8937-8940.In addition, separation may be achieved by selective cystallization,optionally in the presence of a chiral acid or base thereby forming achiral salt.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration fo the invention and are not intended to be limitingthereof.

EXAMPLES Examples 1 and 21N-(2′-Aminosulfonyl-[1,1′]biphenylamino)carbonylmethyl-6-amidinobenzimidazolinone (Example 1) and 1-(2′-Aminosulfonyl-[1,1′]biphenylamino)-carbonylmethyl-5-amidinobenzimidazolinone (Example2)

Preparation of 6—Cyanobenzimidazolinone.

After 4-amino-3-nitrobenzonitrile (3.26 g, 20 mmol) was treated withhydrogen in MeOH (300 mL) in the presence of 5% palladium on activecarbon (1 g) at room temperature for 16 hours, the reaction mixture wasfiltered and the filtrate was concentrated to give3,4-diaminobenzonitrile (2.4 g, 90% yield). A solution of3,4-diaminobenzonitrile (2 g, 15 mmol) in THF (100 mL) was treated withcarbonyldiimidazole (CDI, 3.2 g, 19 mmol) at room temperature for 18hours. The mixture was diluted with EtOAc (150 mL), washed with 1N HCl(30 mL) and brine, and dried over MgSO₄. Filtration and concentrationgave 5-cyanobenzimidazolinone (1.9 g, 80%). ¹H NMR (CD₃OD) δ 7.40 (dd,J=8.1 Hz, J=1.5 Hz, 1H), 7.34 (d, J=1.5 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H);MS: 160.1 (M+H)⁺.

Preparation of 2′-tert-butylaminosulfonyl-[1,1′]biphenylaminocarbonylmethylene chloride.

Acylation of 4-[(o—SO₂NHtBu)-phenyl]aniline (3 mmol) with 2-chloroacetylchloride (4 mmol) in CH₃CN (100 mL) in the presence of K₂CO₃ (4 mmol)was carried out at rt for 16 hours. The mixture was filtered. Thefiltrate was extracted with EtOAc, washed with water, dried over MgSO₄,and concentrated to give the product in almost quantitative yield. ¹HNMR (CD₃OD) δ 8.34 (s, 1H), 8.17 (d, J=8.1 Hz, 1H), 7.67 (d, J=8.4 Hz,2H), 7.59-7.46 (m, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.30 (dd, J=7.6 Hz,J=1.5 Hz, 1H), 4.23 (s, 2H), 3.58 (s, 1H), 1.02 (s, 9H); MS(CI). m/z 381(M+H)⁺.

Preparation of 1N-(2′-tert-butylaminosulfonyl-[1,1′]biphenylamino)carbonylmethyl-6-cyanobenzimidazolinone and1N-(2′-tert-butylaminosulfonyl-[1,1′]biphenylamino)carbonylmethyl-5-cyano-benzimidazolinone.

A solution of 5-cyanobenzimidazolinone (159 mg, 1 mmol) in DMF (5 mL)was treated with NaH (4 mmoL), followed by addition of1N-(2′-tert-butylaminosulfonyl-[1,1′]- biphenylamino)carbonylmethylchloride (380 mg, 1 mmol). The resulting mixture was stirred at roomtemperature for 18 hours, and then was extracted with EtOAc. The organiclayer was washed with water and brine, and dried over MgSO₄, followed bypurification and isolation on HPLC, to give 1N-(2′-tert-butylaminosulfonyl-[1,1l]-biphenylamino)-carbonylmethyl-6-cyanobenzimidazolinone (80 mg, 16%) and 1N-(2′-tert-butylaminosulfonyl-[1,1′]-biphenylamino)-carbonylmethyl-5-cyanobenzimidazolinone (120 mg, 24%). Both regioisomershave ESMS m/z: 465 (M+H). For the 6-cyano isomer: ¹H NMR (CD₃OD) δ 8.11(dd, J=8.4 Hz, J=1.2 Hz, 1H), 7.63 (d, J=8.5 Hz, 2H), 7.63-7.62 (m, 1H),7.51 (td, J=7.8 Hz, J=1.5 Hz, 1H), 7.47 (dd, J=8.4 Hz, J=1.5 Hz, 1H),7.43 (d, J=8.5 Hz, 2H), 7.43-7.42 (m, 1H), 7.32 (dd, J=7.7 Hz, J=1.4 Hz,1H), 7.26 (d, J=8.1 Hz, 1H), 4.82 (s, 2H), 0.99 (s, 9H); ¹³C NMR (CD₃OD)δ 167.28, 156.85, 143.46, 141.60, 139.10, 137.26, 135.85, 133.90,133.05, 131.49, 130.16, 129.53, 128.75, 127.52, 120.59, 120.42, 113.58,110.14, 105.64, 54.99, 44.56, 30.06. For the 5-cyano isomer: ¹H NMR(CD₃OD) δ 8.08 (dd, J=8.1 Hz, J=1.2 Hz, 1H), 7.63-7.56 (m, 3H), 7.49(td, J=7.8 Hz, J=1.5 Hz, 1H), 7.43-7.42 (m, 1H), 7.40 (d, J=7.2 Hz, 2H),7.30 (dd, J=7.6 Hz, J=7.6 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.20 (d,J=8.3 Hz, 1H), 2.01 (s, 2H), 0.99 (s, 9H).

Preparation of 1N-(2′-aminosulfonyl-[1,1′)]-biphenylamino)carbonylmethyl-6-amidinobenzimidazolinone and1N-(2′-aminosulfonyl-[1,1′]-biphenylamino)carbonylmethyl-5-amidinobenzimidazolinone.

A solution of 1N-(2′-tert-butylaminosulfonyl-[1,1′]-biphenylamino)carbonylmethyl-6-cyanobenzimidazolinone (0,16 mmol) inEtOH (10 mL) was saturated with HCl gas and stirred at 0° C. for 16hours. The solution was concentrated to give a residue, which wastreated with NH₄OAc (42 mg, 0.64 mmol) in 2N NH₃ in EtOH (10 mL) at rtfor 16 hours. After the mixture was concentrated, the residue waspurified by HPLC to give the title compound (45 mg, 61%). By usinggeneral Pinner reaction conditions,1N-(2′-tert-butylaminosulfonyl-[1,1′]biphenylamino)carbonylmethyl-5-cyanobenzimidazolinone (0.24 mmol) wasconverted to its amidino derivative (60 mg, 54%). For Example 1: ¹H NMR(CD₃OD) δ 8.08 (dd, J=8.5 Hz, J=1.5 Hz, 1H), 7.62 (dt, J=8.5 Hz, J=1.5Hz, 2H), 7.59-7.55 (m, 3H), 7.50 (td, J=7.8 Hz, J=1.5 Hz, 1H), 7.39 (dt,J=8.4 Hz, J=1.5 Hz, 2H), 7.31 (dd, J=7.3 Hz, J=1.4 Hz, 1H), 7.27 (d,J=8.8 Hz, 1H), 4.82 (s, 2H); ¹³C NMR (CD₃OD) δ 168.44, 167.52, 156.97,143.08, 141.54, 139.03, 137.37, 134.89, 133.66, 132.92, 132.70, 131.26,128.73, 128.61, 123.56, 122.07, 120.58, 110.74, 108.96, 44.63; ESMS: 465(M+H)⁺; HRMS:(M+H) calcd. for C₂₂H₂₀N₆O₄S₁ 465.1345, found 465.1335;Anal.: (C₂₂H₁₈N₄O₁+1.5TFA+0.08HCl+1H₂O) C, H, N, S, F, Cl. For Example2: ¹H NMR (CD₃OD): δ 8.09 (dd, J=7.8 Hz, J=1.2 Hz, 1H), 7.62 (d, J=8.8Hz, 2H), 7.59-7.54 (m, 2H), 7.54-7.50 (m, 2H), 7.40 (dd, J=8.8 Hz, J=2.0Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 4.86 (s, 2H); ESMS: 465.4 (M+H)⁺.

Example 3 1N-[4′-(p-chlorophenyl)thiazolyl-2′-amino)carbonylmethyl-6-amidinobenzimidazolinone

Preparation of 1N-[4′-(p-chlorophenyl)thiazolyl-2′-amino)carbonylmethyl-6-amidinobenzimidazolinone.

A mixture of 1N-Boc-5-cyano-benzoimidazolinone (210 mg, 0.81 mmol),2-(2-chloroacetamido)-4-(p-chlorophenyl)-5- thiazole (255 mg, 0.89mmol), and K₂CO₃ (138 mg, 1.0 mmol) in acetone (10 mL) was stirred at68° C. for 18 hours. The mixture was diluted with EtOAc (150 mL), washedwith water and brine, and dried over MgSO₄. Concentration gave a crudeproduct, which underwent a Pinner reaction, followed by HPLCpurification, to give the product (150 mg, 43.3% for the two steps). ¹HNMR (CD₃OD) δ 7.88 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.4 Hz, 1H), 7.53 (s,1H), 7.41 (s, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.1 Hz, 1H), 4.93(s, 2H); ¹³C NMR (CD₃OD) δ 168.51, 167.09, 159.04, 156.88, 150.20,136.79, 134.66, 134.55, 130.31, 129.76, 128.53, 123.70, 123.17, 122.65,109.89, 109.49, 109.81, 44.01; ESMS: m/z 427.2 (M+H)⁺; HRMS:(M+H) calcd.for C₁₉H₁₅N₆O₂S₁Cl₁ 427.0744, found 427.0743; Anal.:(C₁₉H₁₅N₆O₂S₁Cl₁+1.57TFA+0.22HCl+3H₂O) C, H, N, S, F, Cl.

Example 4 5-Amidino-1N-(1′N-(4′-benzylpiperidino)carbonylmethyl)benzimidazolinone

Preparation of 1N-(4-benzylpiperidino)carbonylmethylchloride.

A solution of 4-benzylpiperidine (17.5 g, 100 mmol) in THF (250 mL) wastreated with K₂CO₃ (14 g, 101 mmol) and chloroacetylchloride (11.3 g,100 mmol) at rt for 2 hours. The reaction mixture was filtered. Thefiltrate was concentrated, and then dissolved in EtOAc and water. The 25organic layer was washed with brine, dried over MgSO₄, and concentratedto give the product (21.6 g, 91.5%). ¹H NMR (CDCl₃) δ 7.32-7.12 (m, 5H),4.09 (s, 2H), 3.79-3.76 (m, 2H), 2,56 (d, J=7.0 Hz, 2H), 1.89-1.80 (m,1H), 1.79-1.71 (m, 4H), 1.28-1.12 (m, 2H).

Preparation of N-(4-benzylpiperidino)carbonylmethylamine.

To a solution of 1N-(4- benzylpiperidino)carbonylmethylchloride (3.3 g,14 mmol) in acetone (48 mL) and water (32 mL) was added NaN₃ (1.4 g, 21mmol), and the resulting mixture was refluxed for 16 hours.

The mixture was concentrated, and the resulting aqueous solution wasextracted with EtOAc. The organic layer was dried over MgSO₄ andconcentrated to give an azide intermediate as an oil. The oil wasdissolved in MeOH (200 mL) and treated with hydrogen in the presence of5% Pd on carbon for 16 hours. The mixture was filtered, and the filtratewas concentrated to give the desired product (2.8 g, 82% for the twosteps) as a colorless oil. ¹H NMR (CDCl₃) δ 7.28 (d, J=7.8 Hz, 2H), 7.20(dd, J=7.3 Hz, J=7-0 Hz, 1H), 7.13 (d, J=7.0 Hz, 2H), 4.59 (d, J=10.3Hz, 1H), 3.74-3.61 (m, 1H), 3.46 (d, J=14.6 Hz, 2H), 2.89 (t, J - 12.4Hz, 1H), 2.59-2.54 (m, 2H), 1.91-1.68 (m, 6H), 1.17-1.13 (m, 2H); MS(CI)m/z 233 (M+H).

Preparation of 4-cyano-2-nitro-1N-(1′N-(4-benzylpiperidino)carbonylmethyl)aniline.

A solution of 4-cyano-2-nitro-benzenechloride (1,82 g, 10 mmol),1N-(4-benzylpiperidino)carbonylmethylamine (2 g, 8.6 ; mmol) and NaHCO₃(0.84 g, 10 mmol) in DMF (10 mL) was stirred at 100° C. for 16 hours.The mixture was cooled to rt, diluted with EtOAc (150 mL), and filtered.The residue was washed with water and EtOAc, and dried by air to givethe product (1.6 g, 49.2%) as a golden solid. The filtrate was washedwith 1N HCl, water and brine, dried over MgSO₄, and concentrated to givemore of the same product (1.1 g, 29%). ¹H NMR (CDCl₃) δ 9.33 (s, 1H),8.55 (d, J=1.5 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.33-7.20 (m, 3H), 7.14(d, J=7.0 Hz, 2H), 6.78 (d, J=9.1 Hz, 1H), 4.65 (d, J=13.5 Hz, 1H), 4.07(d, J=3.7 Hz, 2H),3.71 (d, J=12.8 Hz, 1H), 3.07 (t, J=12.8 Hz, 1H), 2.67(t, J=12.8 Hz, 1H), 2.58 (t, J=6.3 Hz, 2H), 1.85-1.95 (m, 3H), 1.22 (q,J=12.5 Hz, 2H); MS(CI) m/z 379 (M+H).

Preparation of 2-amino-4-cyano-1N-(1′N-(4′-benzylpiperidino)carbonylmethyl)aniline.

A solution of 4-cyano-2-nitro-1N-(1′N-(4′-benzylpiperidino)carbonylmethyl)aniline (1.6 g, 4,23 mmol) in MeOH (120mL) was treated with hydrogen in the presence of 5% Pd on carbon (0.2 g)for 16 hours. The mixture was filtered, and the filtrate wasconcentrated, followed by purification by CC with CH₂Cl₂, to give theproduct (1.33 g, 90%). ¹H NMR (CDCl₃) δ 7.26-7.03 (m, 6H), 6.86 (d,J=1.5 Hz, 1H), 6.38 (d, J=8.1 Hz, 1H), 5.10 (bs, 1H), 4.54 (d, J=12.8Hz, 1H), 3.86 (d, J=4.5 Hz, 2H),3.74 (s, 1H), 3.65 (d, J=12.8 Hz, 1H),3,61 (s, 1H), 3.03 (t, J=12.8 Hz, 1H), 2.61 (d, J=12.8 Hz, 1H),2.53-2.51 (m, 2H), 1.80-1.65 (m, 3H), 1.35-1.05 (m, 2H); MS(CI) m/z 349(M+H).

Preparation of 5-cyano-1N-(1′N-(4′-benzylpiperidino)carbonylmethyl)-benzoimidazolinone.

A solution of 2-amino-4-cyano-1N-(1′N-(4′-benzylpiperidino)carbonylmethyl)aniline (320 mg, 0.94 mmol) in THF (10mL) was treated with 1,1′-carbonyldiimidazole (162 mg, 1 mmol) at rt for4 hours. The mixture was diluted with EtOAc (100 mL) and washed withbrine (50 mL). The organic layer was dried over MgSO₄ and concentratedto give a crude, which was purified on TLC plates with 20% EtOAc inCH₂Cl₂ to give the product (303 mg, 86.2%). ¹H NMR (CDCl₃) δ 7.38-7.12(m, 7H), 6.96 (d, J=8.1 Hz, 1H), 4.69 (dd, J=24.2 Hz, J=16.8 Hz, 2H),4.55 (d, J=13.2 Hz, 1H), 3.92 (d, J=13.5 Hz, 1H),3.49 (s, 1H), 3.11 (t,J=13.2 Hz, 1H), 2.61-2.58 (m, 3H), 1.83-1.72 (m, 3H), 1,26-1.21 (m, 2H);MS(CI) m/z 375.3 (M+H).

Preparation of 5-amidino-1N-(1′N-(4,-benzylpiperidino)carbonylmethyl)-benzoimidazolinone.

By using of Pinner conditions followed by purification on HPLC,5-cyano-1N-(1,N-(4′- benzylpiperidino)carbonylmethyl)benzoimidazolinone(300 mg, 0.8 mmol) was converted to the product (195 mg, 62.5%). ¹H NMR(CD₃OD) δ 7.54 (dd, J=8.3 Hz, J=2.0 Hz, 1H), 7.51 (d, J=1.7 Hz, 1H),7.29-7.14 (m, 6H), 4.94 (d, J=17.1 Hz, 1H), 4.85 (d, J=17.1 Hz, 1H),4.42 (d, J=13.2 Hz,1H), 4.02 (d, J=13.7 Hz, 1H),3.12 (td, J=13.4 Hz,J=2.3 Hz, 1H), 2.64 (td, J=13.3 Hz, J=2.3 Hz, 1H), 2.58 (d, J=7.1 Hz,2H), 1.93-1.81 (m, 1H), 1,78 (d, J=13.4 Hz, 1H), 1.68 (d, J 12.7 Hz,1H), 1.39-1.29 (qd, J=12.7 Hz, J=4.0 Hz, 1H), 1.15 (qd, J=12.7 Hz, J=4.0Hz, 1H); MS(ES) m/z 392.3 (M+H); HRMS:(M+H) calcd. for C₂₂H₂₅N₅O₂392.2087, found 392.2071; Anal.: (C₂₂H₂₅N₅O₂+1.0TFA+0.07HCl).

Example 5 1N-(2′-Aminosulfonyl-[1,1′]biphenylamino)carbonylmethyl-3N-p-hydroxyethylene-6-amidinobenzimidazolinone

Preparation of 3-amino-4N-(β- hydroxyethylene)aminobenzonitrile.

A solution of 4-chloro-3-nitrobenzonitrile (18.3 g, 100 mmol),β-hydroxyethyleneamine(15 g, 245 mmol) and NaHCO₃ (8.4 g, 100 mmol) inMeOH (200 mL) was refluxed for 16 hours. The mixture was treated withhydrogen gas in the presence of 10% Pd on carbon (0.5 g) in MeOH (20 mL)for two days. The reaction mixture was filtered, and the filtrate wasconcentrated. The resulting residue was partitioned in EtOAc and water.The organic layer was neutralized with 1N HCl to pH 7, and then washedwith brine, dried over MgSO₄, and concentrated to give the product (16g, 90.4% for the two steps). MS(CI) m/z 178 (M+H); ¹H NMR (CD₃OD) δ 7.00(dd, J T 8.4 Hz, J=1.8 Hz, 1H), 6.89 (d, J=2.2 Hz, 1H), 6.58 (d, J=8.4Hz, 1H), 3.75 (t, J=5.6 Hz, 2H), 3.28 (t, J=5.5 Hz, 2H).

Preparation of 1N-β-hydroxyethylene-5-cyanobenzoimidazolinone.

After a solution of 3-amino-4N-(β- hydroxyethylene)aminobenzonitrile (6g, 33.7 mmol) in THF (300 mL) was added slowly into a solution of 1,1′-carbonyldiimidazole (6 g, 37 mmol) in THF (200 mL), the resultingmixture was stirred at rt for 24 hours. The mixture was concentrated andthe residue was dissolved in EtOAc (300 mL) and water (100 mL). Theorganic layer was washed with 1N HCl (50 mL), water (50 mL×2) and brine(30 mL×2), dried over MgSO₄, and concentrated to give the product (5.9g, 100%). MS(CI) m/z 204 (M+H); ¹H NMR (CD₃OD) δ 7.26 (dd, J=8.4 Hz,1H), 7.09 (d, J=1.5 Hz, 1H), 6.94 (dd, J=8.1 Hz, J=1.8 Hz, 1H), 4.53 (t,J=8.0 Hz, 2H), 3.93 (t, J=8.0 Hz, 2H).

Preparation of 1N-(21-aminosulfonyl-[1,1′]-biphenylamino)carbonylmethyl-3N-β-hydroxyethylene-6-amidinobenzimidazolinone.

To a solution of 1N-β-hydroxyethylene-5- cyanobenzoimidazolinone (100mg, 0.5 mmol) in acetone (5 mL) was added K₂CO₃ (138 mg, 1 mmol), NaI(75 mg, 0.5 mmol), andN-(2′-tert-butylaminosulfonyl-[1,1′]-biphenylamino)-carbonylmethylchloride (190 mg, 0.5 mmol). After being refluxed for 16hours, the mixture was diluted with EtOAc (100 mL), washed with water(×2) and brine (×2), dried over MgSO₄, and concentrated to give a crudeproduct of the nitrile intermediate. The nitrile was directly carriedout in a Pinner reaction, followed by HPLC purification, to give thetitle compound (130 mg, 51% for the two steps). ¹H NMR (CD₃OD) δ 8.08(dd,J=7.7 Hz, J=1.1 Hz, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.59-7.45 (m, 5H),7.38 (d, J=8.4 Hz, 2H), 7.33 (dd, J=4.0 Hz, J=1.5 Hz, 1H), 7.31 (d,J=4.0 Hz, 1H), 4.62 (t, J=7.7 Hz, 2H), 4.13 (s, 2H), 4.09 (t, J=7.7 Hz,2H); ESMS: m/z 509.4 (M+H)⁺.

Example 6 1N-(1′N-(2′-aminosulfonyl-[1,1′]-biphenylamino)carbonylmethyl)-6-amidinobenzoxazolinone

Preparation of 3-amino-4-hydroxybenzonitrile.

A solution of 4-hydroxy-3-nitrobenzonitrile (10 g, 61 mmol) in MeOH (200mL) was treated with hydrogen gas through a balloon in the presence of5% Pd on active carbon (0.5 g) at room temperature for 24 hours. Themixture was filtered, and the filtrate was concentrated to give theproduct (8.2 g, 100%).

Preparation of 6-cyanobenzoxazolinone.

To a solution of 3-amino-4-hydroxybenzonitrile (8.2 g, 61 mmol) in THF(200 mL) was added 1,1′-carbonyldiimidazole (11.6 g, 72 mmol) and theresulting mixture was stirred at room temperature for 16 hours. Thereaction was then quenched with 1N HCl (50 mL), and the mixture wasextracted with EtOAc (200 mL). The organic layer was washed with brine,dried over MgSO₄, and concentrated to give 6-cyanobenzoxazolinone (9.8g, 100%). ¹H NMR (CDCl₃) δ 7.49 (dd, J=8.4 Hz, J=1.5 Hz, 1H), 7.34 (d,J=1.5 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.15 (d, J=0.9 Hz, 1H).

Preparation of 1N-(1′N-(2′-aminosulfonyl-[1,1′]-biphenylamino)carbonylmethyl-6-amidinobenzoxazolinone.

A mixture of 6-cyanobenzoxazolinone (160 mg, 1 mmol), 1N-(2′-tert-butylaminosulfonyl-[1,1′]- biphenylamino)carbonylmethylenechloride (380 mg, 1 mmol), NaI (75 mg, 0.5 mmol), and K₂CO₃ (207 mg, 1.5mmol) in acetone (10 mL) was refluxed for 4 hours. The mixture wasneutralized with 1N HCl to pH 7 and extracted with EtOAc (200 mL). Theorganic layer was washed with brine, dried over MgSO₄, and concentratedto give a crude. The crude underwent a Pinner reaction, followed by HPLCpurification, to give the title product (232 mg, 50%). ¹H NMR (CD₃OD) δ8.12 (dd, J=7.7 Hz, J=1.8 Hz, 1H), 7.92 (d, J=1.2 Hz, 1H), 7.69 (td, J7.7 Hz, J=2.2 Hz, 1H), 7.62 (dd, J=7.3 Hz, J=1.1 Hz, 1H), 7.57 (d, J=8.4Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.36 (dd, J=7.8 Hz, J=1.6 Hz, 2H), 7.15(d, J=8.4 Hz, 1H), 4.60 (s, 2H); ¹³C NMR (DMSO-d₆) δ 169.12, 164.26,158.60, 154.17, 142.25, 139.74, 139.01, 132.49, 131.54, 131.17, 129.75,129.50, 127.93, 127.33, 125.52, 123.78, 118.42, 117.24, 51.69; ESMS: m/z466.4 (M+H)⁺; HRMS: (M+H) calcd. for C₂₂H₂₀N₅O₅S₁ 466.1185, found466.1157.

Example 7 1N-(N-p-(4′-oxazolyl)phenylamino)carbonylmethyl-6-amidino-benzoxazolinone

Preparation of 1N-[N-p-(4′-oxazolyl)phenylamino)carbonylmethyl-6-cyano-benzoxazolinone.

A mixture of 6-cyanobenzoxazolinone (160 mg, 1 mmol), p-(4-oxazolyl)phenyl chloroacetamido (380 mg, 1 mmol), NaI (150 mg, 1mmol), and K₂CO₃ (138 mg, 1 mmol) in acetone (10 mL) was refluxed for 24hours and then quenched with water (10 mL). The mixture was filtered,and the residue was collected and dried to give a crude product (400mg). ¹H NMR (CDCl₃) δ 7.91 (s, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.63 (d,J=1.8 Hz, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.37 (dd, J=8.8 Hz, J=1.8 Hz,1H), 7.29 (s, 1H), 6.90 (d, J=8.4 Hz, 1H), 4.44 (s, 2H).

Preparation of 1N—(N-p-(4′-oxazolyl)phenylamino)carbonylmethyl-6-amidino-benzoxazolinone.

A crude of 1N-(N-p-(4′-oxazolyl)phenylamino)carbonylmethyl-6-cyano-benzoxazolinone (1 mmol) wascarried on in a Pinner reaction, followed by purification by HPLC, togive the product (100 mg, 26.5%): ¹H NMR (CD₃OD) δ 8.28 (s, 1H), 7.90(d, J=2.6 Hz, 1H), 7.87 (d, J=8.8 Hz, 2H), 7.69 (dd, J=8.8 Hz, J=2.2 Hz,1H), 7.61 (d, J=8.6 Hz, 2H), 7.60 (s, 1H), 7.13 (d, J=8.8 Hz, 1H), 4.57(s, 2H); ESMS: m/z 378 (M+H)⁺; Anal.: (C₁₉H₁₅N₅O₄+0.4TFA+0.85HCl+3H₂O)

Example 8 1N((1′N-(4′N-benzylsulfonylpiperazino)carbonylmethyl-6-amidino-benzoxazolinone

Preparation of N-benzylsulfonylpiperazine.

Acylation of N-Boc-piperazine (1.86 g, 10 mmoL) with benzylsulfonylchloride (1.9 g, 10 mmol) in CH₃CN (20 mL) in the presence of Na₂CO₃(1.01 g, 12 mmol) was carried out at rt for 16 hours. The mixture wasdiluted with EtOAc (150 mL), washed with water (50 mL), dried overMgSO₄, and concentrated to give 1N-Boc-4N-benzylsulfonyl-piperazine (3.3g, 98%). ¹H NMR (CDCl₃) δ 7.39 (bs, 5H), 4.23 (s, 2H), 3.38-3.35 (m,4H), 3.07-3.05 (m, 4H), 1.44 (s, 9H). The Boc-intermediate wasdeprotected with 4M HCl in dioxane (20 mL) at rt for 1 hour. The mixturewas diluted with EtOAc, washed with 1N NaOH and water, dried over MgSO₄,and concentrated to give the product (1.9 g, 81%). ¹H NMR (CDCl₃) δ7.46-7.43 (bs, 5H), 4.22 (s, 2H), 3.11-3.08 (m, 4H), 2.83-2.79 (m, 4H).

Preparation of N-benzylsulfonylpiperazino-2-chloroacetamido.

Acylation of N-benzylsulfonyl-piperazine (1.9 g, 7.9 mmoL) withchloroacetyl chloride (1.13 g, 10 mmol) in CH₃CN (20 mL) in the presenceof Na₂CO₃ (10 mmol) was carried out at rt for 2 hours. The mixture wasdiluted with EtOAc, washed with water, dried over MgSO₄, andconcentrated to give the product (2.34 g, 95%). ¹H NMR (CDCl₃) δ 7.39(bs, 5H), 4.26 (s, 2H), 4.02 (s, 2H), 3.58 (t, J=4.8 Hz, 2H), 3.45 (t,J=4.8 Hz, 2H), 3.14-3.11 (m, 4H).

Preparation of 1N-(1,N-(4′N-benzylsulfonylpiperazino)carbonylmethyl-6-amidino- benzoxazolinone.

A mixture of 6-cyanobenzoxazolinone (80 mg, 0.5 mmol), N-benzylsulfonylpiperazino-2-chloroacetamido (158 mg, 0.5 mmol), and K₂CO₃(138 mg, 1 mmol) in acetone (5 mL) was refluxed for 5 hours. The mixturewas diluted with EtOAc, washed with water, and dried over MgSO₄.Concentration gave a crude, which was purified on TLC plates to give thecyano precursor. The cyano precursor was carried on in a Pinnerreaction, followed by purification by HPLC, to give the product (56 g,20% for two steps). ¹H NMR (DMSO-d₆) δ 9.31 (bs, 1.5H), 9.07 (bs, 1.5H),7.69 (d, J=1.5 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.59 (dd, J=8.8 Hz,J=1.8 Hz, 1H), 7.44-7.37 (m, 5H), 4.90 (s, 2H), 4.48 (s, 2H), 3.57 (bs,2H), 3.47 (bs, 2H), 3.24 (bs, 2H), 3.15 (bs, 2H); ¹³C NMR (DMSO-d₆) δ165.26, 163.88, 153.90, 145.37, 132.03, 130.94, 129.31, 128.43, 128.30,124.17, 123.29, 110.11, 109.43, 54.79, 45.38, 45.08, 44.14, 43.35,41.62, 40.41; ESMS: m/z 458.2 (M+H)⁺: HRMS: (M+H) calcd. forC₂₁H₂₄N₅O₅S₁ 458.1498, found 458.1516.

Example 9 7-amidino-1N-(4-bromophenyl)carbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one

Preparation of 7-cyano-3,4-dihydroquinoxalin-2(1H)-one.

To a solution of 4-chloro-3-nitrobenzonitrile (18.3 g, 100 mmol) andglycine methyl ester•hydrochloride (12.3 g, 100 mmol) in EtOH (150 mL)was added NaHCO₃ (25.2 g, 300 mmol), and the resulting mixture wasrefluxed for 16 hours. The mixture was filtered and the filtrate wasconcentrated. The resulting residue was partitioned in EtOAc and water.The organic layer was neutralized with 1N HCl to pH 7 and then washedwith brine, dried over MgSO₄, and concentrated to give a crude (25 g). Asolution of the crude was hydrogenated in MeOH (500 mL) in the presenceof 10% Pd on carbon (1.5 g) at room temperature for 6 hours. The mixturewas filtered and the filtrate was concentrated to give more of the sameproduct (19.5 g, 100%). ¹H NMR (DMSO-d₆) δ 10.50 (s, 1H), 7.15 (dd,J=8.1 Hz, J=1.8 Hz, 1H), 6.94 (d, J=1.6 Hz, 1H), 6.93 (s, 1H), 6.68 (d,J=8.4 Hz, 1H), 3.90 (d, J=1.1 Hz, 2H); MS(CI) m/z 191 (M+NH₄).

Preparation of 7-cyano-1N-(p-bromophenyl)carbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one.

To a solution of 7-cyano-3,4-dihydroquinoxalin-2(1H)-one (4 mg, 20 mmol)in THF (100 mL) was added K₂CO₃ (152 mg, 1.1 mmoL), 18-crown-6 (230 mg),and 2,4′-dibromoacetophenone (5.54 g, 20 mmol), and the resultingmixture was stirred for 16 hours. The mixture was diluted with EtOAc andfiltered. The residue was washed with EtOAc and water, and dried by airto give the product (2.8 g, 37.8%). The filtrate was washed with brine(50 mL×4), dried over MgSO₄, and concentrated to give a crude material,which was recrystallized in EtOAc (20 mL) to give the product (2 g, 27%)as a white solid. ¹H NMR (DMSO-d₆) δ 8.02 (d, J=8.4 Hz, 2H), 7.83 (d,J=8.4 Hz, 2H), 7.35 (d, J=1.4 Hz, 1H), 7.26 (dd, J=8.1 Hz, J=1.4 Hz,1H), 7.10 (s, 1H), 6.81 (d, J=8.4 Hz, 1H), 5.50 (s, 2H), 4.05 (d, J=1.1Hz, 2H); MS(CI) m/z 370/372 (M+H).

Preparation of 7-amidino-1N-(4′-bromophenyl)carbonylmethyl-3,4-dihydroquinoxalin-2 (1H)-one.

MP: 145-150° C.; MS(ES): m/z 385/387 (M+H); HRMS:(M+H) calcd. forC₁₇H₁₅N₄O₂Br₁ 389.0436, found 389.0418; Anal. (C₁₇H₁₅N₄O₂Br₁+1TFA+HCl)C, H, N, F, Cl; ¹H NMR (CD₃OD) δ 8.02 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.4Hz, 2H), 7.40 (dd, J=8.4 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 6.87 (d, J=8.4Hz, 1H), 5.50 (s. 2H), 4.10 (S, 2H).

Example 10 7-amidino-1N-(31-amino-[1,1′]biphenyl)carbonyl-methyl-3,4-dihydroquinoxalin-2(1H)-one

Preparation of 7-cyano-1N-(33-amino-[1,1′]-biphenyl)carbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one.

A mixture of 7-cyano-1N-(p-bromophenyl)carbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one (370 mg, 1 mmol), 3- aminophenyoboronicacid (137 mg, 1 mmol), NaHCO₃ (210 mg, 2 mmol), and Pd(PPh₃)₄ (60 mg) inTHF (10 mL) and water (1 mL) was refluxed under nitrogen for 16 hours.The mixture was filtered, and the residue was washed with water, CH₂Cl₂,and dried by air to give the product (310 mg, 81.6%). MS(ES): m/z 383.2(M+H); ¹H NMR (CD₃OD) δ 8.22 (d, J=8.4 Hz, 2H), 7.85 (d, J=8.4 Hz, 2H),7.74 (d, J=8.1 Hz, 1H), 7.63-7.58 (m, 2H), 7. 34 (dd, J=8.4 Hz, J=1.4Hz, 1H), 7.22 (dd, J=8.4 Hz, J=1.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.81(d, J=8.0 Hz, 1H),5.54 (s, 2H), 4.08 (s, 2H)

Preparation of 7-amidino-1N-(3′-amino-[1,1′]-biphenyl)carbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one.

By using the general procedure of Pinner reaction, followed by HPLCpurification, the product (157 mg, 50%) was obtained from its cyanoprecursor (300 mg, 0.78 mmol). MP: 85° C.; MS(ES): m/z 200.8 (M+H)²⁺;HRMS:(M+H) calcd. for C₂₃H₂₁N₅O₂ 400.1774, found 400.1780; ¹H NMR(CD₃OD) δ 8.21 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.4 Hz, 2H), 7.51-7.40 (m,4H), 7.20-7.15 (m, 1H), 7.15 (dd, J=2.2 Hz, 1H), 6.88 (d, J=8.4 Hz,1H),5.56 (s, 2H), 4.12 (s, 2H).

Example 11 7-amidino-1N-(41-fluoro-[1,1′]biphenyl)carbonyl-methyl-3,4-dihydroquinoxalin-2(1H)-one

Preparation of 7-cyano-1N-(4′-fluoro-[1,1′]-biphenyl)carbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one.

A mixture of 7-cyano-1N-(p-bromophenyl)carbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one (370 mg, 1 mmol), 4- fluorophenylboronicacid (137 mg, 1 mmol), NaHCO₃ (210 mg, 2 mmol), and Pd(PPh₃)₄ (60 mg) inTHF (10 mL) and water (1 mL) was refluxed under nitrogen for 16 hours.The mixture was filtered, and the filtrate was diluted with EtOAc (100mL). The organic layer was dried with MgSO₄, filtered, and concentratedto give a crude product (340 mg, 88.1%). MS (ES): m/z 386 (M+H); ¹H NMR(CDCl₃) δ 8.13 (d, J=8.1 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 7.63 (dq,J=8.8 Hz, J=2.3 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 1H),6.73 (d, J=8.4 Hz, 2H), 6.75 (s, 1H), 5.41 (s, 2H), 4.19 (s, 2H).

Preparation of 7-amidino-1N-(41-fluoro-[1,1′]-biphenyl)carbonylmethyl-3,4-dihydroquinoxalin-2 (1H)-one.

By using Pinner conditions, followed by HPLC purification, the cyanoprecursor (300 mg, 0.80 mmol) was converted to the product (120 mg, 37%)MP: 138-140° C.; MS(ES): m/z 403 (M+H); ¹H NMR (CD₃OD) δ 8.19 (d, J=8.4Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 1H), 7.73 (dq, J=5.3Hz, J=2.1 Hz, 2H), 7.41 (dd, J=8.4 Hz, J=2.3 Hz, 1H), 7.22 (td, J=8.4Hz, J=2.2 Hz, 2H), 7.15 (d, J=2.2 Hz, 1H), 5.57 (s, 2H), 4.11 (s, 2H);¹³C NMR (CD₃OD) δ 192.51, 165.72, 145.43, 142.16, 135.74, 133.37,128.85, 128.74, 128.64, 127.38, 126.88, 124.34, 115.60, 115.32, 113.80,113.21, 48.48, 45.51; Anal.: (C₂₃H₁₉N₄O₂F₁+1.2TFA+0.05HCl+1H₂O) C, H, N,F, Cl.

Example 12 7-amidino-1N-[1,1′]-biphenylcarbonylmethyl-3,4-

Preparation of 7-amidino-1N-[1,1′]-biphenylcarbonylmethyl-3,4-dihydroquinoxalin-2 (1H)-one.

A mixture of 7—cyano-1N-[(p-bromophenyl)carbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one (185 mg, 0.5 mmol), 4-phenyl-2′-bromoacetophenone (137 mg, 0.5 mmol), K₂CO₃ (210 mg, 2 mmol), and18-crown-6 (20 mg) in THF (10 mL) was stirred for 16 hours. The mixturewas filtered, and the filtrate was diluted with EtOAc (100 mL). Theorganic layer was dried with MgSO₄, filtered, and concentrated to give acrude, which was carried on in a Pinner reaction, followed by HPLCpurification, to give the product (120 mg, 37%) as a solid. MP: 148-150°C.; MS(ES): m/z 385.2 (M+H)⁺; HRMS:(M+H) calcd. for C₂₃H₂₀N₄O₂ 385.1664,found 385.1650; 1H NMR (CD₃OD) δ 8.20 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.0Hz, 2H), 7.71 (d, J=7.4 Hz, 2H), 7.47 (d, J=7.7 Hz, 2H), 7.42-7.33 (m,2H), 7.13 (d, J=1.8 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 5.57 (s, 2H), 4.12(s, 2H); 13C NMR (CD₃OD) δ 192.51, 165.72, 145.43, 142.16, 135.74,133.37, 128.85, 128.74, 128.64, 127.38, 126.88, 124.34, 115.60, 115.32,113.80, 113.21, 48.48, 45.51; Anal.: (C₂₃H₁₉N₄O₂F₁+1.2TFA+0.05HCl+1H₂O)C, H, N, F, Cl.

Examples 13 and 14 7-amidino-1N-(2-tert-butylsulfonamido-[1,1′]biphenyl)carbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one (Example13) and 7-amidino-1N-(2′-sulfonamido-[1,1′]-biphenyl)-carbonylmethyl-3,4-dihyroquinoxalin-2(1H)-one (Example 14)

Preparation of 7-cyano-1N-(4′-sulfonamido-[1,1′]-biphenyl)carbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one.

A mixture of 7-cyano-1N-(p-bromophenyl)carbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one (370 mg, 1 mmol), o-tert-butylsulfonamidophenyoboronic acid (257 mg, 1 mmol), NaHCO₃ (210 mg, 2mmol), and Pd(PPh₃)₄ (90 mg) in THF (20 mL) and water (2 mL) wasrefluxed under nitrogen for 16 hours. The mixture was filtered, and thefiltrate was diluted with EtOAc (100 mL). The organic layer was driedwith MgSO₄, filtered, and concentrated to give a crude, which waspurified on TLC plates to give the product (340 mg, 67.7%). MS(ES): m/z503 (M+H); ¹H NMR (CDCl₃) δ 8.21 (dd, J=8.0 Hz, J=1.5 Hz, 1H), 8.13 (d,J=8.4 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H), 7.64-7.53 (m, 2H), 7.32 (dd,J=8.4 Hz, J=1.5 Hz, 1H), 7.23 (dd, J=8.1 Hz, J=1.5 Hz, 1H), 6.77 (d,J=1.1 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 5.30 (s, 2H), 4.21 (s, 2H), 3.63(s, 1H), 1.08 (s, 9H).

Preparation of 7-amidino-1N-(2′-tert-butylsulfonamido-[1,1′]-biphenyl)-carbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one and7-amidino-1N-(2′-sulfonamido-1,1′]-biphenyl)carbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one.

By using the general procedure of Pinner reaction, followed by HPLCpurification, the cyano precursor (340 mg, 0.67 mmol) was converted toExample 13 (80 mg, 23%) and Example 14 (120 mg, 38.7%), respectively.For Example 13: HRMS:(M+H) calcd. for C₂₇H₃₀N₅O₄S₁ 520.2019, found520.2013; ¹H NMR (CD₃OD) δ 8.16 (d, J=8.8 Hz, 2H), 8.12 (dd, J=1.4 Hz,J=1.4 Hz, 1H), 7.67-7.56 (m, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.41 (dd,J=8.4 Hz, J=1.9 Hz, 1H), 7.33 (dd, J=7.7 Hz, J=1,4 Hz, 1H), 7.16 (d,J=1.8 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 5.58 (s, 2H), 4.13 (s, 2H), 1.07(s, 9H); Anal.: (C₂₇H₃₀N₅O₄S₁+1.1TFA+0.5H₂O) C, H, N, S, F, Cl; ForExample 14: HRMS: (M+H) calcd. for C₂₃H₂₁N₅O₄S₁ 464.1379, found464.1394; ¹H NMR (CD₃OD) δ 8.16 (d, J=8.8 Hz, 2H), 8.11 (d, J=8.4 Hz,1H), 7.62 (d, J=8.4 Hz, 2H), 7.65-7.58 (m, 2H), 7.41 (dd, J=8.4 Hz,J=2.2 Hz, 1H), 7.36 (dd, J=7.3 Hz, J=1,4 Hz, 1H), 7.16 (d, J=2.3 Hz,1H), 6.88 (d, J=8.8 Hz, 1H), 5.58 (s, 2H), 4.13 (s, 2H); ¹³C NMR (CD₃OD)δ 194.11, 167.16, 147.52, 143.64, 143.11, 140.84, 135.23, 133.09,132.95, 131.29, 129.44, 128.89, 128.71, 125.78, 116.77, 115.20, 114.66,54.77, 47.04.

Example 15 1N-(2′-aminosulfonyl-[1,1′]biphenylamino)carbonyl-methyl-7-amidino-3,4-dihydroquinoxalin-2(1H)-one

Preparation of 1N-(2′-aminosulfonyl-[1,1′]-biphenylamino)carbonylmethyl-7-amidino-3,4-dihydroquinoxalin- 2(1H)-one.

A mixture of 7-cyano-3,4-dihydroquinoxalin-2(1H)-one (173 mg, 1 mmol),K₂CO₃ (152 mg, 1.1 mmol), 18-crown-6 (15 mg), and1N-(2′-tert-butylaminosulfonyl-[1,1′]- biphenylamino)carbonylmethylchloride (380 mg, 1 mmol) in DMF (5 mL) was stirred at 80° C. for 16hours. The mixture was diluted with EtOAc, washed with brine (50 mL×4),dried over MgSO₄, and concentrated to give a crude of the nitrilecompound, which underwent a Pinner reaction and HPLC purification, togive the product (210 mg, 44% for the two steps). ESMS: m/z 479.2 (M+H);HRMS:(M+H) calcd. for C₂₃H₂₃N₆O₄S₁ 479.1502, found 479.1491; ¹H NMR(DMSO-d₆) δ 10 34 (s, 1H), 8.93 (s, 2H), 8.56 (s, 2H), 8.02 (d, J=7.8Hz, 2H), 7.62-7.54 (m, 5H), 7.52 (td, J=7.8 Hz, J=1.5 Hz, 1H), 7.34 (d,J=8.4 Hz, 2H), 7. 15 (d, J=8.2 Hz, 1H), 5.18 (s, 1H), 4.80 (s, 2H), 4.06(s, 2H), 3.51 (bs, 2H); ¹³C NMR (CD₃OD) δ 168.44, 167.52, 156.97,143.08, 141.54, 139.03, 137.37, 134.89, 133.66, 132.92, 132.70, 131.26,128.73, 128.61, 123.56, 122.07, 120.58, 110.74, 108.96, 44.63

Example 16 6-amidino-1N-[1,1′-biphenyl)carbonylmethyl-3,4-dihydroquinoxalin-2 (1H)-one

Preparation of 2N-Boc-amino-5-cyanophenylglycin ethyl ester.

To a solution of N-Boc-2-amino-5-cyanoaniline (4.66 g, 20 mmol) in DMF(80 mL) was added K₂CO₃ (2.76 g, 20 mmol), 18- crown-6 (0.3 g), andethyl bromoacetate (3.5 g, 22 mmol). After the mixture was stirred at70° C. for 16 hours, it was cooled to rt, diluted with EtOAc, washedwith water, and dried over MgSO₄. Filtration and concentration, followedby purification by CC with 5% EtOAc in CH₂Cl₂, provided the product (2.4g, 41%). ¹H NMR (CDCl₃) δ 7.67 (d, J=8.4 Hz, 1), 7.15 (dd, i =8.1 Hz,J=1.8 Hz, 1H), 6.86 (d, J=1.8 Hz, 1H), 6.43 (bs, 1H), 4.29 (q, J=7.0 Hz,2H), 3.87 (d, J - 5.5 Hz, 2H), 1.53 (s, 9H), 1.33 (t, J=7.0 Hz, 3H).

Preparation of 6-cyano-3,4-dihydroquinoxalin-2(1H)-one.

N-Boc-2-amino-5-cyanophenylglycin ethyl ester (2.6 g, 8.17 mmol) in MeOH(20 mL) was treated with 4M HCl in dioxane (20 mL) at rt for 16 hours.To the mixture was added Et₂O until no more solid appeared. The solidwas collected, washed with Et₂O, and dried by air to give the product(1.4 g, 82%). ¹H NMR (CD₃COCD₃) δ 7.02 (d, J=8.4 Hz, 1H), 7.00 (d, J=1.8Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 3.89 (s, 2H).

Preparation of 6-amidino-1N-[1,1′]-biphenylcarbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one.

A mixture of 6-cyano-3,4-dihydroquinoxalin-2(1H)-one (171 mg, 0.82mmol), 4-phenyl-2′-bromoacetophenone (277 mg, 1 mmol), K₂CO₃ (140 mg, 1mmol), and 18-crown-6 (30 mg) in DMF (5 mL) was stirred for 16 hours.The mixture was diluted with EtOAc (160 mL) and water (40 mL). Theorganic layer was washed with brine, dried with MgSO₄, filtered,concentrated, and purified on TLC plates to give a 6-cyano-1N-(4′-phenylphenyl)carbonylmethyl-3,4-dihydroquinoxalin-2(1H)-one (110 mg,37%). The cyano precursor was carried on in a Pinner reaction, followedby HPLC purification, to give the product (30 mg, 26%) as a solid. HRMS:(M+H) calcd. for C₂₃H₂₀N₄O₂ 385.1651, found 385-1652; ¹H NMR (CD₃OD) δ8.52 (s, !H), 8.19 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.4 Hz, 2H), 7.71 (d,J=7.0 Hz, 2H), 7.51-7.41 (m, 3H), 7.15 (bs, 1H), 6.87 (d, J=8.4 Hz, 1H),5.57 (s, 2H), 4.07 (s, 2H).

Example 17 1-N-[1,1′]Biphenylcarbonyl)ethyl-6-amidinobenzoxazolinone

Preparation of 3-[1,1′]-biphenyl-1,2-propen-3-one.

trans-Benzyl(chloro)bis-(triphenylphosphine)palladium(II) (0.24 mmol,0.18 g) and vinyltributyl tin (47.31 mmol, 15 g) were added to asuspension of [1,1′]-biphenylcarbonyl chloride (45.49 mmol, 9.82 g) in30 mL chloroform. The reaction mixture was warmed to 60° C. for ca. 15h. Then the reaction mixture was pourred into diethyl ether and washedwith water and half saturated KF solution. The tin salts were filteredthe organics were dried over MgSO₄ and concentrated in vacuo. The crudematerial was purified by standard chromatographic technique to give theproduct as a white solid. LRMS: m/z 209(M+H, 100). ¹H NMR (CDCL₃,300MHz) δ 8.50 (d, 2H), 7.71 (d, 2H), 7.63 (d, 2H), 7.45 (m, 3H), 7.20 (m,1H), 6.49 (dd, 1H), 5.95 (dd, 1H).

Preparation of 1N-([1,1′]-biphenylcarbonyl)ethyl-6-amidinobenzoxazolinone.

6—Cyanobenzoxazolinone (5.0 mmol, 0.80 g) was synthesized as previouslydescribed and added to a solution of 3-[1,1′]- biphenyl-1,2-propen-3-one(5.0 mmol, 1.04 g) and triethylamine (10.00 mmol, 1.39 mL) in 40 mLacetonitrile. The reaction mixture was warmed from ambient temperatureto 77° C. for 2 h. The reaction mixture was concentrated and placedunder high vaccum to give the crude product. The crude material was useddirectly. LRMS: m/z 386 (M+NH4,100). The 1N-[[1,1′]-biphenylcarbonyl]ethyl-6-cyanobenzoxazolinone was converted to itscorresponding benzamidine via the Pinner synthesis and amidination withammonium carbonate to give crude 1N-[4-biphenylcarbonyl]ethyl-6-amidinobenzoxazolinone. The crude product waspurified by standard reverse phase HPLC. LRMS: m/z 386(M+H,100). HRMS:calcd for C₂₃H₂₀N₃O₃, 386.150467; found, 386.150040.

Example 18 1-([1,1′]-Biphenylcarbonyl)ethyl-6-amidino-3N-methylbenzimidazolinone

6—Cyano-3N-methylbenzimidazolone (2.31 mmol, 0.40 g) which wassynthesized similarly to its benzimidazolone analog except that1N-methyl-2-amino-4-cyanoaniline was used as starting material and3-(4-biphenyl)-1,2-propen-3-one (2.31 mmol, 0.48 g) were combined in 20mL of acetonitrile to form a suspension. The reaction mixture was warmedto 77° C. and heated for 24 h. The reaction mixture was concentrated andthe resulting residue was purified by standard chromatographic techniqueto give 1-(4-biphenylcarbonyl)ethyl-6- cyanobenzimidazolinone. LRMS: m/z382(M+H,100). The purified material was subjected to Pinner conditionsfollowed by reaction with ammonium carbonate to give the title compound1- (4-biphenylcarbonyl) ethyl-6-amidino-3N- methylbenzimidazolinone. ¹HNMR(CDCL₃,300 MHz): δ 9.12 (bs, 2H), 8.77 (bs, 2H), 8.01 (d, 2H), 7.78(m, 3H). 7.72 (d, 2H), 7.43 (complex, 5H), 4.21 (t, 2H), 3.56 (t, 2H),3.35 (s, 3H). LRMS: m/z 399.4(M+H,100). HRMS: calcd for C₂₄H₂₃N₄O₂,399.182101; found, 399.181375.

Example 19 1-(1,1′]-biphenylcarbonyl)ethyl-6-amidinobenzimidazolinone

6—Cyano-3N-acetylbenzimidazolone (1.47 mmol, 0.29 g) which wassynthesized similarly to its benzimidazolone analog except that1N-acetyl-2-amino-4-cyanoaniline was used as starting material and3-(4-biphenyl)-1,2-propen-3-one (1.37 mmol, 0.29 g) were combined in 15mL of acetonitrile to form a suspension. The reaction mixture was warmedto 77° C. and heated for 24 h. The reaction mixture was concentrated andthe resulting residue was purified by standard chromatographic techniqueto give crude 1-(4-biphenylcarbonyl)ethyl-6-cyano-3N-acetylbenzimidazolinone. The crude material was subjected to Pinnerconditions followed by reaction with ammonium carbonate to give thetitle compound 1-(4- biphenylcarbonyl)ethyl-6-amidinobenzimidazolinone.LRMS: m/z 385 (M+H,100). HRMS: calcd for C₂₃H₂₁N₄O₂, 385.166451; found,385.167149.

Example 20 1N-(4-Bromophenylcarbonyl)ethyl-6-amidinabenzoxazolinone

Preparation of 1N-(4-Bromophenylcarbonyl)ethyl-6- cyanobenzoxazolinone.

6—Cyanobenzoxazolinone (7.06 mmol, 1.13 g) was synthesized as previouslydescribed (Example 6) and added to a solution of4-bromo-beta-chloropropiophenone (7.77 mmol, 1.92 g) and triethylamine(17.66 mmol, 2.46 mL) in 100 mL acetonitrile. The reaction mixture waswarmed to 77° C. for 24 h. The reaction mixture was allowed to cool toambient temperature at which time the product precipitated from thesolution as a white solid. LRMS: m/z 390(M+NH4). The 1N-(4-bromophenylcarbonyl)ethyl-6-cyanobenzoxazolinone was used directly andwas converted to its corresponding benzamidine via the Pinner synthesisfollowed by amidination with ammonium carbonate to give crude1N-(4-bromophenylcarbonyl)ethyl-6-amidinobenzoxazolinone. The crudeproduct was purified by standard reverse phase HPLC. ¹H NMR(dmso-d₆,300MHz): δ 9.30 (bs, 2H), 9.10 (bs, 2H), 7.85 (m, 4H), 7.71 (d, 2H), 7.58(s, 1H), 4.15 (t, 2H), 3.58 (t, 2H). LRMS: m/z 390(M+H,100). HRMS: calcdfor C₁₇H₁₄BrN₃O₃, 388.029678; found, 388.030885.

Example 211N-14-(2-Aminosulfonylphenyl)pyridin-2-yl]aminocarbonylmethyl-6-amidinobenzoxazolinone

Preparation of 2-Aminocarbonylmethylchloro-4-(2′-tert-butylsulphonylphenyl)pyridine.

Chloroacetyl chloride (8.23 mmol, 0.66 mL) was dripped into a solutionof 2-amino-5-(2′-tert- butylsulphonylphenyl)pyridine (8.23 mmol, 2.51 g)in 80 mL THF. The reaction mixture was stirred overnight at ambienttemperature. The reaction mixture was concentrated under reducedpressure to give 2-aminocarbonylmethylchloro-5-(2′-tert-butylsulphonylphenyl)pyridine as white solid. LRMS: m/z 382(M+H).

Preparation of 1N-[4-((2′-tert-Butylaminosulphonylphenyl)pyridin-1-yl)aminocarbonylmethyl]-6-amidinobenzoxazolinone.

6—Cyanobenzoxazolinone (5.33 mmol, 0.85 g) was added to a solution of2-aminocarbonylmethylchloro-5-(2′-tert-butylaminosulphonylphenyl)pyridine (5.33 mmol, 2.22 g), sodium iodide(2.67 mmol, 0.40 g) and triethylamine (15.99 mmol, 2.23 mL) in 50 mLTHF. The reaction mixture was warmed to reflux temperature for 24 h.Then the reaction mixture was concentrated and purified via standardflash chromotographic technique to give 1N-[4-((2′-tert-butylaminosulphonylphenyl)pyridin-1-yl)aminocarbonylmethyl]-6-cyanobenzoxazolinone. LRMS: m/z 506 (M+H,100). The 1N-[4-((2′-tert-butylaminosulphonylphenyl)pyridin-l-yl)aminocarbonylmethyl]-6-cyanobenzoxazolinone was converted to itscorresponding benzamidine via the Pinner synthesis and amidination withammonium carbonate to give crude 1N-[5-((2′-tert-butylsulphonylphenyl)pyridin-1-yl)aminocarbonylmethyl]-6-amidinobenzoxazolinone. The crude product was purified by standardreverse phase HPLC. ¹H NMR (DMSO-d₆, 300 MHz): δ 11.21 (s, 1H), 9.26 (s,2H), 8.91 (s, 2H), 8.30 (d, 1H), 7.98 (m, 2H), 7.77 (m, 2H), 7.62 (m,3H), 7.36 (m, 2H), 4.82 (bs, 2H). LRMS: m/z 467(M+H). HRMS: calcd forC₂₁H₁₇N₆O₄, 467.113765; found, 467.114384.

Example 22 1N-(4-Morpholinosulfonamidophenyl)aminocarbonylmethyl-6-amidinobenzoxazolinone

Preparation of 4-Nitrobenzenemorpholinosulfonamide.

Morpholine (44.31 mmol, 3.86 mL) was dripped into a cooled (0° C.)solution of 4-nitrobenzenesulfonyl chloride (14.77 mmol, 3.27 g) in 100mL methylene chloride. The reaction mixture was allowed to warm toambient temperature overnight. Then the reaction mixture wasconcentrated under reduced pressure and diluted with EtOAC. The organicswere washed 3×50 mL water, dried over MgSO₄ and concentrated in vacuo togive a yeloow solid. The crude 4-nitrobenzenemorpholinesulfonamide wasused directly after a few hours under high vacuum. LRMS: m/z 290(M+NH4).The crude nitro compound was reduced catalytically with 10% palladium oncarbon at 1 atm of hydrogen to give 0.43 g of crude 4-morpholinesulfonamidoaniline. LRMS: m/z 243 (M+H,100).

Preparation of 4- Aminocarbonylmethylchlorobenzenemorpholinosulfonamide.

Chloroacetyl chloride (1.78 mmol, 0.14 mL) was dripped into a solutionof 4-morpholinesulfonamidoaniline (1.78 mmol, 0.43 g) and triethylamine(3.73 mmol, 0.52 mL) in 100 mL THF. The reaction mixture was stirred for20 h at ambient temperature. The reaction mixture was concentrated underreduced pressure and worked up with water and brine washings to give thecrude 4- aminocarbonylmethylchlorobenzenemorpholinesulfonamide. LRMS:m/z 319 (M+H).

Preparation of 1N-(4- Morpholinosulfonamidophenyl)carbonylmethyl-6-amidinobenzoxazolinone.

6—Cyanobenzoxazolinone (0.82 mmol, 0.13 g) was added to a solution 4-aminocarbonylmethylchlorobenzenemorpholinesulfonamide (0.82 mmol, 0.26g) and triethylamine (1.80 mmol, 0.25 mL) in 10 mL .2 acetonitrile. Thereaction mixture was warmed to 80° C. for 24 h. Then the reactionmixture was concentrated and purified via -standard flashchromotographic technique to give 1N-(4-morpholinesulfonamidophen-1-yl)aminocarbonylmethyl-6-cyanobenzoxazolinone. LRMS: m/z 460 (M+NH4). The 1N-(4-morpholinesulfonamidophen-1-yl)aminocarbonylmethyl-6-cyanobenzoxazolinone was converted to its corresponding benzamidine viathe Pinner synthesis and amidination with ammonium carbonate to give thecrude 1N-(4- morpholinesulfonamidophenyl)aminocarbonylmethyl-6-amidinobenzoxazolinone. The crude product was purified by standardreverse phase HPLC. ¹H NMR (DMSO-d₆, 300 MHz): δ 11.10 (s, 1H), 9.21(bs, 2H), 8.72 (bs, 2H), 7.91 (m, 3H), 7.82 (m, 4H), 4.53 (s, 2H), 3.62(m, 4H), 2.88 (m, 4H). LRMS: m/z 460 (M+H). HRMS: calcd for C₂₁H₂₁N₅O₆S,460.130418; found, 460.130002.

Example 101 3-(3-methoxy-(2′-aminosulfonyl-[1,1′]biphenyl-1-aminocarbonyl)methyl-5-amidino-2-indolinone

To a stirred solution of 3-(21-aminosulfonyl-(1,1′]-biphenylaminocarbonyl)methyl-5-cyanoindole (300 mg, 0.62 mmol) in 10 mLof t-BuOH was added NBS (120 mg, 0.67 mmol) at rt and it stirred for 18h. The reaction was diluted with water and extracted with ethyl acetate(3×), dried with sodium sulfate, filtered and concentrated in vacuo. Theyellow residue was chromatographed via flash Silica Gel using 1:1hexanes:ethylacetate as the eluant. Fractions were collected andconcentrated in vacuo to afford of desired product in 35% yield (130 mg,0.22 mmol). The bromo compound was then dissolved in dry MeOH cooled to−20° C. and saturated with HCl(g). Resulting solution was allowed towarm up to rt over 18 h. The reaction was concentrated in vacuo. Theresulting residue was dissolved in dry MeOH and after addition ofammonium carbonate the flask sealed and stirred for 18 at rt. Themixture was filtered through Celite®, rinsed with MeOH, and methylenechloride. Concentration under vacuo afforded a mixture of products.Separation and purification was accomplished via prep. HPLC to affordthe 3-methoxy, and the 3-amino 2-oxyindoles. ¹H NMR (CD₃OD) δ ppm 3.05(s, 3H), 3.25 (qd, 2H, J=15 Hz), 7.21(d,1H, J=7.5 Hz), 7.32 (m, 3H),7.51 (m, 4H), 7.82 (d, J=7.5 Hz), 8.03, (m, 2H). HRMS (M+H)⁺ forC₂₄H₂₄N₅O₅S calc: 494.149816; found: 494.149536.

Example 102 3-(3-amino-(2′aminosulfonyl-[1,1′]-biphenylaminocarbonyl)methyl-5-amidino-2-indolinone

Prepared and purified using the procedure from Example 101. ¹H NMR(CD₃0D) δ ppm 3.25 (qd, 2H, J=15 Hz), 7.21(d,1H, J=7.5 Hz), 7.32 (m,3H), 7.51 (m, 4H), 7.82 (d, J=7.5 Hz), 8.03, (m, 2H). HRMS (M+H)⁺ forC₂₃H₂₃N₆O₄S calc: 479.148813; found: 479.149389.

Example 103 3-(3-hydroxy-(2′-aminosulfonyl-[1,1′]-biphenylaminocarbonyl)methyl-5-amidino-2-indolinone

Preparation of 3-(2′-aminosulfonyl-[1,1′]-biphenylaminocarbonyl)methyl-5-cyanoindole.

To a stirred soluiton of 5-cyano-3-acetic acid indole (1.0 g, 50 mmol),BOP (3.32 g, 7.5 mmol) in DMF (35 mL) was added4-(2-aminosulfonyl)phenyl-2-aminobenzene (1.48 mg, 6.0 mmol) and heatedat 50° C. for 3 h. The reaction was diluted with water, extracted withethyl acetate, washed with 10% HCl, sodium bicarbonate, brine, water,dried with magnesium sulfate, filtered and concentrated in vacuo toafford 420 mg of product. The t-butyl group was removed in TFA refluxfor 1 h. Purified via silica gel using 100% ethyl acetate as the eluentto afford 530 mg of product. LRMS (M+H)⁺ 431.

Preparation of 3-(2′-aminosulfonyl-[1,1′]-biphenylaminocarbonyl)methyl-5-amidinoindole.

The 5-cyanoindole was subjected to the Pinner conditions followed byammonium carbonate in dry MeOH. Purification was accomplished via prepHPLC to afford 264 mg of product. HRMS calc 448.14337; found 448.142583.

Preparation of 2-[3-(3-hydroxy-(2′-aminosulfonyl-[1,1′]-biphenylaminocarbonyl)methyl]-5-amidino-2-indolinone.

To a stirred solution of 3-(21-aminosulfonyl-[1,1′]-biphenylaminocarbonyl)methyl-5-amidinoindole (1.03 g, 2.1 mmol) in 30 mLof t-BuOH was added NBS (374 mg, 2.1 mmol) and stirred for 18 h at rtunder a nitrogen atmosphere. The mixture was concentrated in vacuo andredissolved in dry MeOH/MeOAc (1:4) Ammonium carbonate (x's) was addedthe flask sealed and stirred at rt for 48 h. Resulting mixture wasfiltered through Celite®, rinsed with MeOH and methylene chloride andthe filtrate was concentrated in vacuo. Purification was accomplishedvia prep HPLC to afford 60 mg of desired product as the TFA salt. ¹H NMR(DMSO-d₆) δ ppm 3.05 (q, 2H, J=11.5 Hz), 6.98 (d, 1H, J=6.0 Hz) 7.18 (s,2H), 7.22 (m, 3H), 7.41 (d, 1H, J=6.0 Hz), 7.40 (s, 1H), 7.58 (m, 2H),7.75 (d, 1H, J=6.0 Hz), 7.82 (s, 1H), 8.0 (d, 1H, J=6.0 Hz)8.67 (bs,2H), 9.15 (bs, 2H), 10.05 (bs, 1H), 10.78 (s, 1H). HRMS (M+H)⁺ forC₂₃H₂₂N₅O₅S calc: 480.134166; found: 480.135777.

Example 104 3-(3′-hydroxy-(2-chioro-(2′-aminosulfonyl)-[1,1′]-biphenylaninocarbonyl)methyl-5-amidino-2-indolinone

Prepared using the procedure of Example 103. ¹H NMR (CD₃OD) δ ppm 3.25(qd, 2H, J=9 Hz), 7.04 (d, 1H, J=9 Hz), 7.23(m, 2H), 7.43 (nd, 1H, J=1.8Hz), 7.58(m, 3H), 7.78(dd,1H, J=1.8 Hz, J=9.0 Hz), 7.83(nd, 1H, J=1.8Hz), 8.04 (dd, 1H, J=1.8 Hz, J=9.0 Hz). HRMS (M+H)⁺ for C₂₃H₂₁ClN₅O₅Scalc.: 514.095194; found: 514.094336.

Example 105 3-(3′-amino-(2-chloro-(2′-aminosulfonyl)-[1,1′]-biphenylaminocarbonyl)methyl-5-amidino-2-indolinone

Isolated from the preparation of Example 104. ¹H NMR (CD₃OD) δ ppm 3.05(qd, 2H, J=9.0 Hz), 7.09 (d, 1H, J=6.0 Hz), 7.25 (t, 2H, J=6.0 Hz), 7.45(m, 4H), 7.81 (d, 1H, J=6.0 Hz), 8.03 (m, 2H). HRMS (M+H)⁺ forC₂₃H₂₁ClN₆O₄S calc.: 513.111178; found: 513.113281.

Example 201 3-(2-chloro-(2′-aminosulfonyl)-[1,1′]biphenyl-3′-aminocarbonyl)methyl-5-amidino-2-indolinone

Isolated from the preparation of Example 104. ¹H NMR (CD₃OD) δ ppm 3.6(s, 2H), 7.15 (d, 1H, J=7.2 Hz), 7.23 (d, 1H, J=4.8 Hz), 7.32 1H, J=4.8Hz), 7.5 (m, 5H), 7.81 (d, 1H, J=7.2 Hz), 8.03 (s, 1H). HRMS (M+H)⁺ forC₂₃H₁₉ClN₅O₄S calc.: 496.084629; found: 496.084051.

Example 202 3-(2-bromo-(21-aminosulfonyl)-[1,1′]biphenyl-3′-aminocarbonyl)methyl-5-amidino-2-indolinone

Prepared using the procedure of Example 201. ¹H NMR (CD₃OD) δ ppm 3.58(s, 2H), 7.12 (d, 1H, J=9.0 Hz), 7.21 (d, 1H, J=7.2 Hz), 7.36 (s, 2H),7.58 (m,2H), 7.8 (d, 1H, J=9.0 Hz), 8.03 (d, 1H, J=7.2 Hz), 8.08 (s,1H). HRMS (M+H)⁺ for C₂₃H₁₉BrN₅O₄S calc.: 540.03442; found: 540.032207.

Example 203 3-(2-fluoro-(2′-aminosulfonyl)-[1,1′]biphenyl-3′-aminocarbonyl)methyl-5-amidino-2-indolinone

Prepared using the procedure of Example 201. ¹H NMR (CD₃OD) δ ppm 3.58(q, 2H, J=9.0 Hz), 7.04 (d, 1H, J=9.0 Hz), 7.16 (d, 1H, J=7.2 Hz), 7.21(d, 1H, J=7.0 Hz), 7.23 (d, 1H, J=7.0 Hz), 7.58 (m, 3H), 7.81 (d, 1H,J=9.0Hz), 7.89 (s, 1H), 8.12 (m, 2H). HRMS (M+H)⁺ for C₂₃H₁₉FN₅O₄S calc.:480.114179; found: 480.114566.

Example 2043-(2′-aminosulfonyl)-[1,1′]biphenyl-3′-aminocarbonyl)methyl-5-amidino-2-indolinone

Prepared using the procedure of Example 201. HRMS (M+H)⁺ forC₂₃H₂₀FN₅O₄S calc.: 462.123601; found: 462.123950.

TABLE 1

Ex # FIG. Am J^(b) Z′—A—B MS 1 A m NH2′-aminosulfonyl-[1,1′]-biphenylamino 465.1345 2 A p NH2′-aminosulfonyl-[1,1′]-biphenylamino 465.4 3 A m NH4′-chlorophenyl-thiazol-2-yl 427.0743 4 A p NH 4′-benzylpiperidino392.2071 5 A m N—(CH₂)₂OH 2′-aminosulfonyl-[1,1′]-biphenylamino 509.4 6A m O 2′-aminosulfonyl-[1,1′]-biphenylamino 466.1157 7 A m O4-(oxazol-5′-yl)phenylamino 378 8 A m O 4′-(benzylsulfonyl)piperidino458.1516 9 B m — 4′-bromophenyl 387.0286 10 B m —2′-amino-[1,1′]-biphenyl 400.1780 11 B m — 4′-fluoro-[1,1′]-biphenyl 40312 B m — [1,1′]-biphenyl 385.1650 13 B m —2′-t-butylaminosulfonyl-[1,1′]-biphenylamino 520.2013 14 B m —2′-aminosulfonyl-[1,1′]-biphenylamino 464.1396 15 B NH2′-aminosulfonyl-[1,1′]-biphenylamino 479.1491 16 B p — [1,1′]-biphenyl385.1651 17 C m O [1,1′]-biphenyl 386 18 C m NCH₃ [1,1′]-biphenyl 399 19C m NH [1,1′]-biphenyl 385 20 C m O 4-bromophenyl 390 21 A m O5-(2′-aminosulfonyl-phenyl)pyridin-2-ylamino 467 22 A m O4-(morpholinosulfonyl)phenylamino 460

Unless otherwise defined, all stereochemistry is (+/−).

TABLE 2

Ex # R Z—A—B MS 101 methoxy 2′-aminosulfonyl-[1,1′]- 494.1495 biphenyl-aminocarbonylmethyl 102 amino 2′-aminosulfonyl-[1,1′]- 479.1488biphenyl- aminocarbonylmethyl 103 hydroxy 2′-aminosulfonyl-[1,1′]-480.1358 biphenyl- aminocarbonylmethyl 104 hydroxy 2′-aminosulfonyl-2-514.0943 chloro-[1,1′]-biphenyl- aminocarbonylmethyl 105 amino2′-aminosulfonyl-2- 513.1133 chloro-[1,1′]-biphenyl- aminocarbonylmethyl

Unless otherwise defined, all stereochemistry is (+/−).

TABLE 3

Ex # A—B MS 201 2′-aminosulfonyl-2- 496.0840 chloro-[1,1′]-biphenyl- 2022′-aminosulfonyl-2- 540.03221 bromo-[1,1′]-biphenyl- 2032′-aminosulfonyl-2- 480.1146 fluoro-[1,1′]-biphenyl- 2042′-aminosulfonyl-2- 462.1230 [1,1′]-biphenyl-

Unless otherwise defined, all stereochemistry is (+/−).

The following table contains representative examples of the presentinvention. Each entry in the table is intended to be paired with eachformulae at the start of the table.

TABLE 4

Ex # A B 301 phenyl 2-(aminosulfonyl)phenyl 302 phenyl2-(methylaminosulfonyl)phenyl 303 phenyl 1-pyrrolidinocarbonyl 304phenyl 2-(methylsulfonyl)phenyl 305 phenyl 4-morpholino 306 phenyl2-(1′-CF₃-tetrazol-2-yl)phenyl 307 phenyl 4-morpholinocarbonyl 3082-pyridyl 2-(aminosulfonyl)phenyl 309 2-pyridyl2-(methylaminosulfonyl)phenyl 310 2-pyridyl 1-pyrrolidinocarbonyl 3112-pyridyl 2-(methylsulfonyl)phenyl 312 2-pyridyl 4-morpholino 3132-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 314 2-pyridyl4-morpholinocarbonyl 315 3-pyridyl 2-(aminosulfonyl)phenyl 316 3-pyridyl2-(methylaminosulfonyl)phenyl 317 3-pyridyl 1-pyrrolidinocarbonyl 3183-pyridyl 2-(methylsulfonyl)phenyl 319 3-pyridyl 4-morpholino 3203-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 321 3-pyridyl4-morpholinocarbonyl 322 2-pyrimidyl 2-(aminosulfonyl)phenyl 3232-pyrimidyl 2-(methylaminosulfonyl)phenyl 324 2-pyrimidyl1-pyrrolidinocarbonyl 325 2-pyrimidyl 2-(methylsulfonyl)phenyl 3262-pyrimidyl 4-morpholino 327 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl328 2-pyrimidyl 4-morpholinocarbonyl 329 5-pyrimidyl2-(aminosulfonyl)phenyl 330 5-pyrimidyl 2-(methylaminosulfonyl)phenyl331 5-pyrimidyl 1-pyrrolidinocarbonyl 332 5-pyrimidyl2-(methylsulfonyl)phenyl 333 5-pyrimidyl 4-morpholino 334 5-pyrimidyl2-(1′-CF₃-tetrazol-2-yl)phenyl 335 5-pyrimidyl 4-morpholinocarbonyl 3362-Cl-phenyl 2-(aminosulfonyl)phenyl 337 2-Cl-phenyl2-(methylaminosulfonyl)phenyl 338 2-Cl-phenyl 1-pyrrolidinocarbonyl 3392-Cl-phenyl 2-(methylsulfonyl)phenyl 340 2-Cl-phenyl 4-morpholino 3412-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 342 2-Cl-phenyl4-morpholinocarbonyl 343 2-F-phenyl 2-(aminosulfonyl)phenyl 3442-F-phenyl 2-(methylaminosulfonyl)phenyl 345 2-F-phenyl1-pyrrolidinocarbonyl 346 2-F-phenyl 2-(methylsulfonyl)phenyl 3472-F-phenyl 4-morpholino 348 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl349 2-F-phenyl 4-morpholinocarbonyl 350 2,5-diF-phenyl2-(aminosulfonyl)phenyl 351 2,5-diF-phenyl 2-(methylaminosulfonyl)phenyl352 2,5-diF-phenyl 1-pyrrolidinocarbonyl 353 2,5-diF-phenyl2-(methylsulfonyl)phenyl 354 2,5-diF-phenyl 4-morpholino 3552,5-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 356 2,5-diF-phenyl4-morpholinocarbonyl

Unless otherwise defined, all stereochemistry is (+/−).

Utility

The compounds of this invention are useful as anticoagulants for thetreatment or prevention of thromboembolic disorders in mammals. The term“thromboembolic disorders” as used herein includes arterial or venouscardiovascular or cerebrovascular thromboembolic disorders, including,for example, unstable angina, first or recurrent myocardial infarction,ischemic sudden death, transient ischemic attack, stroke,atherosclerosis, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary and cerebral arterialthrombosis, cerebral embolism, kidney embolisms, and pulmonaryembolisms. The anticoagulant effect of compounds of the presentinvention is believed to be due to inhibition of factor Xa or thrombin.

The effectiveness of compounds of the present invention as inhibitors offactor Xa was determined using purified human factor Xa and syntheticsubstrate. The rate of factor Xa hydrolysis of chromogenic substrateS2222 (Kabi Pharmacia, Franklin, Ohio) was measured both in the absenceand presence of compounds of the present invention. Hydrolysis of thesubstrate resulted in the release of pNA, which was monitoredspectrophotometrically by measuring the increase in absorbance at 405nM. A decrease in the rate of absorbance change at 405 nm in thepresence of inhibitor is indicative of enzyme inhibition. The results ofthis assay are expressed as inhibitory constant, K_(i).

Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant,Km, for substrate hydrolysis was determined at 25° C. using the methodof Lineweaver and Burk. Values of K_(i) were determined by allowing0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend,Ind.) to react with the substrate (0.20 mM-1 mm) in the presence ofinhibitor. Reactions were allowed to go for 30 minutes and thevelocities (rate of absorbance change vs time) were measured in the timeframe of 25-30 minutes. The following relationship was used to calculateK_(i) values:

(v _(o) −v _(s))/v _(s) =I/(K _(i)(1+S/K _(m)))

where:

v_(o) is the velocity of the control in the absence of inhibitor;

v_(s) is the velocity in the presence of inhibitor;

I is the concentration of inhibitor;

K_(i) is the dissociation constant of the enzyme:inhibitor complex;

S is the concentration of substrate;

K_(m) is the Michaelis constant.

Using the methodology described above, a number of compounds of thepresent invention were found to exhibit a K_(i) of ≦15 μM, therebyconfirming the utility of the compounds of the present invention aseffective Xa inhibitors.

The antithrombotic effect of compounds of the present invention can bedemonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. Inthis model, rabbits weighing 2-3 kg anesthetized with a mixture ofxylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. Asaline-filled AV shunt device is connected between the femoral arterialand the femoral venous cannulae. The AV shunt device consists of a pieceof 6-cm tygon tubing which contains a piece of silk thread. Blood willflow from the femoral artery via the AV- shunt into the femoral vein.The exposure of flowing blood to a silk thread will induce the formationof a significant thrombus. After forty minutes, the shunt isdisconnected and the silk thread covered with thrombus is weighed. Testagents or vehicle will be given (i.v., i.p., s.c., or orally) prior tothe opening of the AV shunt. The percentage inhibition of thrombusformation is determined for each treatment group. The ID50 values (dosewhich produces 50% inhibition of thrombus formation) are estimated bylinear regression.

The compounds of formula (I) may also be useful as inhibitors of serineproteases, notably human thrombin, plasma kallikrein and plasmin.Because of their inhibitory action, these compounds are indicated foruse in the prevention or treatment of physiological reactions, bloodcoagulation and inflammation, catalyzed by the aforesaid class ofenzymes. Specifically, the compounds have utility as drugs for thetreatment of diseases arising from elevated thrombin activity such asmyocardial infarction, and as reagents used as anticoagulants in theprocessing of blood to plasma for diagnostic and other commercialpurposes.

Some compounds of the present invention were shown to be direct actinginhibitors of the serine protease thrombin by their ability to inhibitthe cleavage of small molecule substrates by thrombin in a purifiedsystem. In vitro inhibition constants were determined by the methoddescribed by Kettner et al. in J. Biol. Chem. 265, 18289-18297 (1990),herein incorporated by reference. In these assays, thrombin- mediatedhydrolysis of the chromogenic substrate S2238 (Helena Laboratories,Beaumont, Tex.) was monitored spectrophotometrically. Addition of aninhibitor to the assay mixture results in decreased absorbance and isindicative of thrombin inhibition. Human thrombin (Enzyme ResearchLaboratories, Inc., South Bend, Ind.) at a concentration of 0.2 nM in0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000,was incubated with various substrate concentrations ranging from 0.20 to0.02 mM. After 25 to 30 minutes of incubation, thrombin activity wasassayed by monitoring the rate of increase in absorbance at 405 nm whicharises owing to substrate hydrolysis. Inhibition constants were derivedfrom reciprocal plots of the reaction velocity as a function ofsubstrate concentration using the standard method of Lineweaver andBurk. Using the methodology described above, some compounds of thisinvention were evaluated and found to exhibit a K_(i) of less than 15μm, thereby confirming the utility of the compounds of the presentinvention as effective Xa inhibitors-

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. Theseinclude other anti- coagulant or coagulation inhibitory agents,anti-platelet or platelet inhibitory agents, thrombin inhibitors, orthrombolytic or fibrinolytic agents.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of Formula I that, when administered alone or incombination with an additional therapeutic agent to a mammal, iseffective to prevent or ameliorate the thromboembolic disease conditionor the progression of the disease.

By “administered in combination” or “combination therapy” it is meantthat the compound of Formula I and one or more additional therapeuticagents are administered concurrently to the mammal being treated. Whenadministered in combination each component may be administered at thesame time or sequentially in any order at different points in time.Thus, each component may be administered separately but sufficientlyclosely in time so as to provide the desired therapeutic effect. Otheranticoagulant agents (or coagulation inhibitory agents) that may be usedin combination with the compounds of this invention include warfarin andheparin, as well as other factor Xa inhibitors such as those describedin the publications identified above under Background of the Invention.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function such as byinhibiting the aggregation, adhesion or granular secretion of platelets.Such agents include, but are not limited to, the various knownnon-steroidal anti- inflammatory drugs (NSAIDS) such as aspirin,ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam,diclofenac, sulfinpyrazone, and piroxicam, including pharmaceuticallyacceptable salts or prodrugs thereof. Of the NSAIDS, aspirin(acetylsalicyclic acid or ASA), and piroxicam are preferred. Othersuitable anti-platelet agents include ticlopidine, includingpharmaceutically acceptable salts or prodrugs thereof. Ticlopidine isalso a preferred compound since it is known to be gentle on thegastro-intestinal tract in use. Still other suitable platelet inhibitoryagents include IIb/IIIa antagonists, thromboxane-A2-receptor antagonistsand thromboxane-A2-synthetase inhibitors, as well as pharmaceuticallyacceptable salts or prodrugs thereof.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the granular secretion of plasminogen activator inhibitor-1and/or serotonin) and/or fibrin formation are disrupted. A number ofthrombin inhibitors are known to one of skill in the art and theseinhibitors are contemplated to be used in combination with the presentcompounds. Such inhibitors include, but are not limited to, boroargininederivatives, boropeptides, heparins, hirudin and argatroban, includingpharmaceutically acceptable salts and prodrugs thereof. Boroargininederivatives and boropeptides include N-acetyl and peptide derivatives ofboronic acid, such as C-terminal a-aminoboronic acid derivatives oflysine, ornithine, arginine, homoarginine and correspondingisothiouronium analogs thereof. The term hirudin, as used herein,includes suitable derivatives or analogs of hirudin, referred to hereinas hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitorsinclude compounds described in Kettner et al., U.S. Pat. No. 5,187,157and European Patent Application Publication Number 293 881 A2, thedisclosures of which are hereby incorporated herein by reference. Othersuitable boroarginine derivatives and boropeptide thrombin inhibitorsinclude those disclosed in PCT Application Publication Number 92/07869and European Patent Application Publication Number 471,651 A2, thedisclosures of which are hereby incorporated herein by reference.

The term thrombolytics (or fibrinolytic) agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator,anistreplase, urokinase or streptokinase, including pharmaceuticallyacceptable salts or prodrugs thereof. The term anistreplase, as usedherein, refers to anisoylated plasminogen streptokinase activatorcomplex, as described, for example, in European Patent Application No.028,489, the disclosure of which is hereby incorporated herein byreference herein. The term urokinase, as used herein, is intended todenote both dual and single chain urokinase, the latter also beingreferred to herein as prourokinase.

Administration of the compounds of Formula I of the invention incombination with such additional therapeutic agent, may afford anefficacy advantage over the compounds and agents alone, and may do sowhile permitting the use of lower doses of each. A lower dosageminimizes the potential of side effects, thereby providing an increasedmargin of safety.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of factor Xa. Such compoundsmay be provided in a commercial kit, for example, for use inpharmaceutical research involving factor Xa. For example, a compound ofthe present invention could be used as a reference in an assay tocompare its known activity to a compound with an unknown activity. Thiswould ensure the experimenter that the assay was being performedproperly and provide a basis for comparison, especially if the testcompound was a derivative of the reference compound. When developing newassays or protocols, compounds according to the present invention couldbe used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving factor Xa. For example, the presence of factor Xa in anunknown sample could be determined by addition of chromogenic substrateS2222 to a series of solutions containing test sample and optionally oneof the compounds of the present invention. If production of pNA isobserved in the solutions containing test sample, but no compound of thepresent invention, then one would conclude factor Xa was present.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide- polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of the compound of Formula I and about 1 to 7.5milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 10 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 5milligrams per dosage unit.

Where the compounds of Formula I are administered in combination with ananti-platelet agent, by way of general guidance, typically a dailydosage may be about 0.01 to 25 milligrams of the compound of Formula Iand about 50 to 150 milligrams of the anti-platelet agent, preferablyabout 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3milligrams of antiplatelet agents, per kilogram of patient body weight.

Where the compounds of Formula I are adminstered in combination withthrombolytic agent, typically a daily dosage may be about 0.1 to 1milligrams of the compound of Formula I, per kilogram of patient bodyweight and, in the case of the thrombolytic agents, the usual dosage ofthe thrombolyic agent when administered alone may be reduced by about70-80% when administered with a compound of Formula I.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of Formula I and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained- release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise that as specifically describedherein.

What is claimed as new and desired to be secured by Letter Patent ofUnited States is:
 1. A compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:one of W, W¹, W², and W³ is C—D and the remaining are C—R¹; D isselected from CN, C(═NR⁷)NR⁸R⁹, NHC(═NR⁷)NR⁸R⁹, NR⁸CH(═NR⁷), C(O)NR⁸R⁹,and (CH₂)_(t)NR⁸R⁹; Q is CO or CS; R is selected from C₁₋₆ alkyl, NH₂,NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, OH, C₁₋₆ alkoxy, C₁₋₆ alkoxy-C₁₋₄ alkyl,(CH₂)_(t)NR⁸R⁹, 5-6 membered aromatic heterocyclyl-C₁₋₄ alkyl, andaryl-C₁₋₄ alkyl, wherein the aromatic heterocyclyl and aryl groups aresubstituted with 0-1 R⁴; R^(a) is selected from H, C₁₋₆ alkyl,C(O)R^(2b), 5-6 membered aromatic heterocyclyl-C₁₋₄ alkyl, and aryl-C₁₋₄alkyl, wherein the aromatic hetercyclyl and aryl groups are substitutedwith 0-1 R⁴; R^(b) is H or C₁₋₂ alkyl; R^(d) is selected from H, OH,NH₂, C₁₋₂ alkyl, and C₁₋₂ alkyl-OH, Z is selected from a bond, C₁₋₄alkylene, (CH₂)_(r)O(CH₂)_(r), (CH₂)_(r)NR³(CH₂)_(r),(CH₂)_(r)C(O)(CH₂)_(r), (CH₂)_(r)C(O)O(CH₂)_(r),(CH₂)_(r)OC(O)(CH₂)_(r), (CH₂)_(r)C(O)NR³(CH₂)_(r),(CH₂)_(r)NR³C(O)(CH₂)_(r), (CH₂)_(r)OC(O)O(CH₂)_(r),(CH₂)_(r)OC(O)NR³(CH₂)_(r), (CH₂)_(r)NR³C(O)O(CH₂)_(r),(CH₂)_(r)NR³C(O)NR³(CH₂)_(r), (CH₂)_(r)S(O)_(p)(CH₂)_(r),(CH₂)_(r)SO₂NR³(CH₂)_(r), (CH₂)_(r)NR³SO₂(CH₂)_(r), and(CH₂)_(r)NR³SO₂NR³(CH₂)_(r), provided that Z does not form a N—N, N—O,N—S, NCH₂N, NCH₂O, or NCH₂S bond with the groups to which it isattached; R¹, at each occurrence, is selected from H, F, Cl, Br, I,(CF₂)_(r)CF₃, OR², NR²R^(2a), C(O)R^(2b), (CF₂)_(r)CO₂R², S(O)₂R^(2b),NR²C(O)R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), C₃₋₆ carbocyclic residuesubstituted with 0-2 R⁴, and 5-10 membered heterocyclic systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S and substituted with 0-2 R⁴; R¹′, at each occurrence, isselected from H, C₁₋₃ alkyl, F, Cl, Br, I, —CN, —CHO, (CF₂)_(r)CF₃,(CH₂)_(r)OR², NR²R^(2a), C(O)R^(2c), OC(O)R², (CF₂)_(r)CO₂R^(2c),S(O)_(p)R^(2b), NR²(CH₂)_(r)OR², CH(═NR^(2c))NR²R^(2a), NR²C(O)R^(2b),NR²C(O)NHR^(2b), NR²C(O)₂R^(2a), OC(O)NR^(2a)R^(2b), C(O)NR²R^(2a),C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a), NR²SO₂R^(2b), C₃₋₆ carbocyclicresidue substituted with 0-2 R^(4b), and 5-10 membered heterocyclicsystem containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S substituted with 0-2 R^(4b); R¹″, at eachoccurrence, is selected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a),S(O)R^(2b), S(O)₂R^(2b), and SO₂NR²R^(2a); R², at each occurrence, isselected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(4b), and 5-6 membered heterocyclic systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S and substituted with 0-2 R^(4b); R^(2a), at each occurrence, isselected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residuesubstituted with 0-2 R^(4b), and 5-6 membered heterocyclic systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S and substituted with 0-2 R^(4b); alternatively, R² and R^(2a),together with the atom to which they are attached, combine to form a 5or 6 membered saturated, partially saturated or unsaturated ringsubstituted with 0-2 R^(4b)and containing from 0-1 additionalheteroatoms selected from the group consisting of N, O, and S; R^(2b) isselected from CF₃, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclicresidue substituted with 0-2 R^(4b), and 5-6 membered heterocyclicsystem containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S and substituted with 0-2 R^(4b); R^(2c), ateach occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆ alkyl,benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6membered heterocyclic system containing from 1-4 heteroatoms selectedfrom the group consisting of N, O, and S substituted with 0-2 R^(4b);R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;A is selected from: C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁴,and 5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S and substituted with0-2 R⁴; B is selected from: Y and X—Y; X is selected from C₁₋₄ alkylene,—CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—, —C(═NR¹″)—, —CR²(NR¹″R²)—,—CR²(OR²)—, —CR²(SR²)—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —S(O)_(p)—,—S(O)_(p)CR²R^(2a)—, —CR²R^(2a)S(O)_(p)—, —S(O)₂NR²—, —NR²S(O)₂—,—NR²S(O)₂CR²R^(2a)—, —CR²R^(2a)S(O)₂NR²—, —NR²S(O)₂NR²—, —C(O)NR²—,—NR²C(O)—, —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—,—CR²R^(2a)NR²C(O)—, —NR²C(O)O—, —OC(O)NR²—, —NR²C(O) NR²—, —NR²—,—NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—, and —OCR²R^(2a)—; Y isselected from: (CH₂)_(r)NR²R^(2a), provided that X—Y do not form a N—N,O—N, or S—N bond, C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a),and 5-10 membered heterocyclic system containing from 1-4 heteroatomsselected from the group consisting of N, O, and S substituted with 0-2R⁴a; R⁴, at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², F,Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a),(CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a),CH(═NR²)NR²R^(2a), CH(═NS(O)₂R⁵)NR²R^(2a), NHC(═NR²)NR²R^(2a),C(O)NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃, NCH₂R¹″, OCH₂R¹″, SCH₂R¹″,N(CH₂)₂(CH₂)_(t)R¹′, O(CH₂)₂(CH₂)_(t)R¹′, and S(CH₂)₂(CH₂)_(t)R¹′;alternatively, one R⁴ is a 5-6 membered aromatic heterocycle containingfrom 1-4 heteroatoms selected from the group consisting of N, O, and S;R^(4a), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR²,(CH₂)_(r)—F, (CH₂)_(r)—Br, (CH₂)_(r)—Cl, I, C₁₋₄ alkyl, —CN, NO₂,(CH₂)_(r)NR²R^(2a), (CH₂)_(r)NR²R^(2b), (CH₂)_(r)C(O)R^(2c),NR²C(O)R^(2b), C(O)NR²R^(2a), C(O)NH(CH₂)₂NR²R^(2a), NR²C(O)NR²R^(2a),CH(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a),NR²SO₂—C₁₋₄ alkyl, C(O)NHSO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and(CF₂)_(r)CF₃; alternatively, one R^(4a) is a 5-6 membered aromaticheterocycle containing from 1-4 heteroatoms selected from the groupconsisting of N, O, and S; R^(4b), at each occurrence, is selected fromH, ═O, (CH₂)_(r)OR³, F, Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂,(CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³, (CH₂)_(r)C(O)OR^(3c),NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O)NR³R^(3a), CH(═NR³)NR³R^(3a),NH³C(═NR³)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl,NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl,S(O)_(p)-phenyl, and (CF₂)_(r)CF₃; R⁵, at each occurrence, is selectedfrom CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzylsubstituted with 0-2 R⁶; R⁶, at each occurrence, is selected from H, OH,(CH₂)_(r)OR², F, Cl, Br, I, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r)NR²R^(2a),(CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), NR²C(O)NR²R^(2a), CH(═NH)NH₂,NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₄ alkyl; R⁷, ateach occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl,C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl,C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl,C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl,phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl; R⁸, at eachoccurrence, is selected from H, C₁₋₆ alkyl and (CH₂)n-phenyl; R⁹, ateach occurrence, is selected from H, C₁₋₆ alkyl and (CH₂)n-phenyl; p, ateach occurrence, is selected from 0, 1, and 2; r, at each occurrence, isselected from 0, 1, and 2; and, t, at each occurrence, is selected from0 and 1; provided that A—B is other than benzyl-thiazolidin-2,4-dione.2. A compound according to claim 1, wherein; one of W, W¹, W², and W³ isC—D and the remaining are C—R¹; Q is CO; Z is selected from a CH₂O,OCH₂, CH₂NH, NHCH₂, CH₂C(O), C(O)CH₂, C(O)NH, C(O)NH, CH₂S(O)₂,S(O)₂(CH₂), SO₂NH, and SO₂NH; B is selected from: Y, X—Y, and NR²R^(2a);Y is selected from one of the following carbocyclic and heterocyclicsystems which are substituted with 0-2 R^(4a); phenyl, piperidinyl,piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl,pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole,1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4- oxadiazole,1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole,1,3,4-triazole, benzofuran, benzothiofuran, indole, benzimidazole,benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, andisoindazole; Y may also be selected from the following bicyclicheteroaryl ring systems:

K is selected from O, S, NH, and N.
 3. A compound according to claim 2,wherein;

or stereoisomer or pharmaceutically acceptable salt thereof, wherein; Dis C(═NR⁷)NR⁸R⁹; A is selected from: piperidinyl, piperazinyl, C₅₋₆carbocyclic residue substituted with 0-2 R⁴, and 5-6 membered heteroarylcontaining from 1-4 heteroatoms selected from the group consisting of N,O, and S and substituted with 0-2 R⁴; and, B is selected from: Y andX—Y.
 4. A compound according to claim 3, wherein; Y is selected from oneof the following carbocyclic and heterocyclic systems which aresubstituted with 0-2 R⁴a; phenyl, piperidinyl, piperazinyl, pyridyl,pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,benzimidazole, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole,1,2,4-oxadiazole, 1,2,5- oxadiazole, 1,3,4-oxadiazole,1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5- thiadiazole,1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, and1,3,4-triazole.
 5. A compound according to claim 1, wherein the compoundis selected from:2-[3-(3-methoxy-(2′-aminosulfonyl-[1,1′]biphenyl-1-aminocarbonyl)methyl]-5-amidino-2-indolinone;2-[3-(3-amino-(2′-aminosulfonyl-[1,1′]-biphenylaminocarbonyl)methyl]-5-amidino-2-indolinone;2-[3-(3-hydroxy-(2′-aminosulfonyl-[1,1′]-biphenylaminocarbonyl)methyl]-5-amidino-2-indolinone;2-[3-(3′-hydroxy-(2-chloro-(2′-aminosulfonyl)-[1,1′]-biphenylaminocarbonyl)methyl]-5-amidino-2-indolinone;2-[3-(3′-amino-(2-chloro-(2′-aminosulfonyl)-[1,1′]-biphenylaminocarbonyl)methyl]-5-amidino-2-indolinone;2-(3-(2-chloro-(2′-aminosulfonyl)-[1,1′]biphenyl-3′-aminocarbonyl)methyl)-5-amidino-2-indolinone;2-(3-(2-bromo-(2′-aminosulfonyl)-[1,1′]biphenyl-3′-aminocarbonyl)methyl)-5-amidino-2-indolinone;2-(3-(2-fluoro-(2′-aminosulfonyl)-[1,1′]biphenyl-3′-aminocarbonyl)methyl)-5-amidino-2-indolinone; and,2-(3-(2′-aminosulfonyl)-[1,1′]biphenyl-3′-aminocarbonyl)methyl)-5-amidino-2-indolinone.
 6. A pharmaceutical composition, comprising: apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound according to claim 1 or a pharmaceuticallyacceptable salt thereof.
 7. A pharmaceutical composition, comprising: apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound according to claim 2 or a pharmaceuticallyacceptable salt thereof.
 8. A pharmaceutical composition, comprising: apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound according to claim 3 or a pharmaceuticallyacceptable salt thereof.
 9. A pharmaceutical composition, comprising: apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound according to claim 4 or a pharmaceuticallyacceptable salt thereof.
 10. A pharmaceutical composition, comprising: apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound according to claim 5 or a pharmaceuticallyacceptable salt thereof.
 11. A method for treating a thromboembolicdisorder, comprising: administering to a patient in need thereof atherapeutically effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof.
 12. A method for treating athromboembolic disorder, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound according toclaim 2 or a pharmaceutically acceptable salt thereof.
 13. A method fortreating a thromboembolic disorder, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundaccording to claim 3 or a pharmaceutically acceptable salt thereof. 14.A method for treating a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound according to claim 4 or a pharmaceuticallyacceptable salt thereof.
 15. A method for treating a thromboembolicdisorder, comprising: administering to a patient in need thereof atherapeutically effective amount of a compound according to claim 5 or apharmaceutically acceptable salt thereof.